Fluorotaxoids

ABSTRACT

The invention relates to fluorinated second generation taxoid compounds, pharmaceutical formulations thereof, and their use for inhibiting the growth of cancer cells in a mammal.

The present application claims priority to U.S. Provisional ApplicationNo. 60/707,665 filed on Aug. 12, 2005, which application is incorporatedherein by reference in its entirety.

The present invention was made with government support under Grant No.R01 GM 42798 awarded by the National Institute of General MedicalSciences and Grant No. R01 CA10331 awarded by the National CancerInstitute. The United States government has certain rights in thisinvention.

BACKGROUND OF THE INVENTION

First generation taxoid compounds such as paclitaxel (Taxol®) anddocetaxel (Taxotere®) have gained prominence as some of the mostefficacious anticancer drugs. See E. K. Rowinsky, Annual Review ofMedicine 1997, 48, 353; M. Suffness, Taxol Science and Applications; CRCPress: New York, 1995.

Second generation taxoid compounds with orders of magnitude higherpotency have also been developed. See U.S. Pat. Nos. 6,096,909,6,100,411, 6,458,976, and 6,500,858 to I. Ojima; G. I. Georg, T. Chen,I. Ojima, and D. M. Vyas (Eds.), “Taxane Anticancer Agents Basic Scienceand Current Status,” ACS Symp. Series 583; American Chemical Society,Washington, D.C., 1995); I. Ojima, et al, Bioorg. Med. Chem. Lett.,1999, 9, 3423-3428; I. Ojima, et al, J. Med. Chem., 1996, 39, 3889-3896;and I. Ojima, G. D. Vite, K.-H. Altmann (Eds.), “Anticancer Agents:Frontiers in Cancer Chemotherapy,” ACS Symp. Series 796, AmericanChemical Society, Washington, D.C., 2001.

While these and other second generation taxoids have shown a high degreeof efficacy in the treatment of various forms of cancer, there is acontinuing need for improving the activity, metabolic stability, andmode of action of these compounds. There is a particular need to improvethe efficacy of second generation taxoid compounds against multi-drugresistance (MDR) in the treatment of cancer. There is also a need fornew taxoid compounds having less acute side effects and higher metabolicstability.

SUMMARY OF THE INVENTION

These, and other objectives as will be apparent to those of ordinaryskill in the art, have been achieved by providing a compound having theformula:

wherein:R¹ represents an alkyl, alkenyl, alkylamino, dialkylamino, or alkoxygroup having one to six carbon atoms; a non-aromatic carbocyclic alkylor alkenyl group having three to seventeen ring carbon atoms; acarbocyclic aryl group having six to eighteen ring carbon atoms; anon-aromatic heterocyclic group having three to seventeen ring carbonatoms or a heterocyclic aryl group having five to seventeen ring carbonatoms, wherein said cyclic groups can be unfused or fused, andunsubstituted or substituted;R² represents a hydrogen; alkyl, alkenyl, alkoxy, alkenyloxy, acyloxy,alkylthio, alkenylthio, alkylamino or dialkylamino having one to sixcarbon atoms; halogen; fluoroallyl group having one to three fluorineatoms and one to three carbon atoms; hydroxyl; carboxyl; amino or azido;R³ and R⁵ both represent hydrogen, or R³ and R⁵ are linked as a cycliccarbonate;R⁴ represents an alkyl or alkenyl group having one to six carbon atoms;or a cycloalkyl or cycloalkenyl group having three to seven ring carbonatoms; andR⁶ represents a fluorovinyl, difluorovinyl, or trifluorovinyl grouphaving the formula

wherein R⁷, R⁸, and R⁹ each independently represent a hydrogen or fluorogroup, provided that at least one of R⁷, R⁸, and R⁹ represents a fluorogroup.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising the fluorotaxoid composition.

The invention is further directed to a method for inhibiting the growthof cancer cells in a mammal in need thereof, the method comprisingadministering to the mammal an effective amount of the fluorotaxoidcompound described above.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention relates to second generation fluorotaxoidcompounds. The fluorotaxoid compounds contain a fluorovinyl,difluorovinyl, or trifluorovinyl group at the C3′ position of a secondgeneration taxoid compound.

In a preferred embodiment, the taxoid compounds of the invention arerepresented by the formula:

In formula (1), R¹ represents a hydrocarbon group selected from analkyl, alkenyl, alkylamino, dialkylamino, or alkoxy group having one tosix carbon atoms; a non-aromatic carbocyclic alkyl or alkenyl grouphaving three to seventeen ring carbon atoms; an aryl group having six toeighteen ring carbon atoms; or a non-aromatic heterocyclic group havingthree to seventeen ring carbon atoms; or a heteroaryl group having fiveto seventeen ring carbon atoms. These acyclic and cyclic hydrocarbongroups may be attached to the fluorotaxoid at any carbon position.

Some examples of suitable straight-chained alkyl groups include methyl,ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl.

Some examples of suitable branched alkyl groups include iso-propyl,iso-butyl, sec-butyl, t-butyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl (isopentyl), 1,1-dimethylpropyl, 1,2-dimethylpropyl,2,2-dimethylpropyl (neopentyl), 1-methylpentyl, 2-methylpentyl,3-methylpentyl, and 4-methylpentyl.

Some examples of suitable straight-chained alkenyl groups include vinyl,2-propen-1-yl, 2-buten-1-yl, 3-buten-1-yl, 2-penten-1-yl, 3-penten-1-yl,1,3-pentadien-1-yl, 4-penten-1-yl, 2-hexen-1-yl, 3-hexenyl,4-hexen-1-yl, and 5-hexen-1-yl.

Some examples of suitable branched alkenyl groups include propen-2-yl,1-buten-2-yl, 2-buten-2-yl, 1-buten-3-yl, 1-penten-2-yl, 1-penten-3-yl,1-penten-4-yl, 2-penten-2-yl, 2-penten-3-yl, 2-penten-4-yl,1-buten-3-methyl-2-yl, 1-buten-3-methyl-3-yl, 2-buten-2-methyl-1-yl,2-buten-2-methyl-3-yl, 2-buten-2-methyl-4-yl, 2-buten-2-5 methylenyl,2-buten-2,3-dimethyl-1-yl, 1-hexen-2-yl, 1-hexen-3-yl, 1-hexen-4-yl,1-hexen-5-yl, 2-hexen-2-yl, 2-hexen-3-yl, 2-hexen-4-yl, 2-hexen-5-yl,3-hexen-2-yl, 3-hexen-3-yl, 1-penten-3-methyl-2-yl,1-penten-3-methyl-3-yl, 1-penten-3-methyl-4-yl, 2-penten-3-methyl-2-yl,and 2-penten-3-methyl-4-yl.

Some examples of suitable alkylamino groups include methylamino,ethylamino, n-propylamino, iso-propylamino, n-butylamino,sec-butylamino, iso-butylamino, tert-butylamino, n-pentylamino,iso-pentylamino, neo-pentylamino, n-hexylamino, 2,3-dimethylbutylamino,cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino,cycloheptylamino, 2-hydroxyethylamino,2-(2-hydroxyethyleneoxy)-ethylamino, 2-methoxyethylamino,2-ethoxyethylamino, and 3-hydroxypropylamino.

Some examples of suitable dialkylamino groups include dimethylamino,methylethylamino, methyl(n-propyl)amino, methyl(iso-propylamino),methyl(n-butyl)amino, methyl(iso-butyl)amino, methyl(n-pentyl)amino,methyl(iso-pentyl)amino, methyl(neopentyl)amino, diethylamino,ethyl(n-propyl)amino, ethyl(iso-propylamino), ethyl(n-butyl)amino,ethyl(iso-butyl)amino, di(n-propyl)amino, and di(iso-propyl)amino.

Some examples of suitable alkoxy groups include methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, n-hexoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 2,2-dimethylbutoxy,2,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, cyclopropyloxy,cyclobutyloxy, 2,4-dimethylcyclobutyloxy, cyclohexyloxy,cyclopropylmethyloxy, cyclohexylmethyloxy, and phenoxy.

The non-aromatic carboxylic alkyl or alkenyl groups of R¹ have three toseventeen ring carbon atoms. Some examples of suitable non-aromaticcarboxylic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl. Some examples of suitable non-aromaticcarboxylic alkenyl groups include cyclobutenyl, cyclobutadienyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, andcycloheptadienyl.

The cyclic groups described above can be fused or unfused. The totalnumber of carbon atoms include carbon atoms from fused rings.

A preferred unfused carbocyclic aryl group is phenyl. Some examples ofsuitable fused aryl groups include naphthyl, phenanthryl, anthracenyl,triphenylenyl, chrysenyl, and pyrenyl.

The heterocyclic aryl groups have five to seventeen atoms in the ringwith one or more heteroatoms, preferably nitrogen, sulfur, or oxygenatoms. Some examples of suitable heteroaryl groups include pyridinyl,pyrimidinyl, triazinyl, imidazolyl, benzimidazolyl, pyrrolyl,cinnolinyl, phthalazinyl, quinazolinyl, purinyl, 2,6-naphthyridinyl,1,8-naphthyridinyl, quinolinyl, isoquinolinyl, carbazolyl, oxazolyl,thiophenyl, thiazolyl, furyl, pyridazinyl, pyrazolyl,1,4-diazanaphthalenyl, indolyl, pyrazinyl, 4,5-diazaphenanthrene, andbenzoxazole.

R¹ can also be a non-aromatic heterocyclic group. Some examples ofsuitable non-aromatic heterocyclic groups include piperidinyl,piperidinyl-N-oxide, N-methylpiperidinyl, piperazinyl,1-methylpiperazinyl, piperazinyl-N-oxide, 1-acetylpiperazinyl,1-(o-tolyl)piperazinyl, homopiperazinyl, and morpholino.

The cycloalkyl, cycloalkenyl, aryl, heteroaryl and non-aromaticheterocyclic rings described above for R¹ can be substituted with any ofthe hydrocarbon groups thus far described.

Some examples of hydrocarbyl-substituted cycloalkyl groups include2-methylcyclopropyl, 2-ethylcyclopropyl, 2-methylcyclobutyl,3-methylcyclobutyl, 2-methylcyclopentyl, 2,3-dimethylcyclopentyl,3-iso-propylcyclopentyl, 2,6-dimethylcyclohexyl, 4-(t-butyl)cyclohexyl,2-vinylcyclohexyl, 3-allylcyclopentyl, 3,4-diallylcyclopentyl,1-(4-pyridinyl)piperidinyl, 1-(4-pyridinylmethyl)piperidinyl,4-(4-pyridinyl)piperidinyl, 4-(4-pyridinyl)piperazin-1-yl, andbicyclohexyl groups.

Some examples of hydrocarbyl-substituted cycloalkenyl groups include3-methyl-3-cyclopenten-1-yl, 3,4-dimethyl-3-cyclopenten-1-yl,2-iso-propyl-2-cyclopenten-1-yl, 2,3-diethyl-2-cyclopenten-1-yl,4-vinyl-1-cyclohexen-1-yl, 3,4-diethyl-3-cyclopenten-1-yl, and3,4-diallyl-3-cyclopenten-1-yl groups.

Some examples of hydrocarbyl-substituted aryl groups include tolyl,mesityl, xylyl, cumenyl, cymenyl, 3,5-di(t-butyl)phenyl,2-methylnaphthyl, 2-vinylphenyl, 2-vinylbenzyl, 2-vinylnaphthyl,4-cyclohexylphenyl, biphenyl, 4-(4-piperidinyl)pyridinyl, andp-terphenyl groups.

Some examples of hydrocarbyl-substituted heteroaryl groups include2-methylpyridin-1-yl, 2-ethylpyridin-1-yl, 3-vinylimidazol-1-yl,2-methylimidazol-1-yl, 2-methylquinoxalin-1-yl, 1-allylbenzotriazolyl,2,2′-bipyridyl, 4,4′-bipyridyl, 4-methylpyrazinyl,4-(pyridinylmethyl)-pyridinyl, 4-benzylpyrazinyl, nicotinamidyl,2-methylfuranyl, 5-methylfurfurylamino, 2-methylthiopheneyl,4-methyloxazolyl, 2,5-diphenyl-4-methyloxazolyl, and 4-methylthiazolylgroups.

Alternatively, the cycloalkyl, cycloalkenyl, aryl, heteroaryl andnon-aromatic heterocyclic rings described above for R¹ can besubstituted with a halogen, nitro, hydroxylcarboxyl, amino or azidogroup.

In formula (1), R² can also represent any of the hydrocarbon groupsdescribed above with regard to R¹. For example, R² can represent alkyl,such as methyl; alkenyl; alkoxy, such as methoxy; alkenyloxy; acyloxy;alkylthio; alkenylthio; alkylamino; or dialkylamino having one to sixcarbon atoms. Preferably, the hydrocarbon group contains a maximum oftwo carbon atoms. Alternatively, R² can also represent hydrogen; ahalogen, such as iodo, bromo, chloro or fluoro; or fluoroalkyl havingone to three fluorine atoms and one to three carbon atoms, for example,trichloromethyl; hydroxyl; amino; carboxyl; or azido.

R³ and R⁵ both preferably represent hydrogen, or R³ and R⁵ togetherrepresent a cyclic carbonate (i.e., —O—C(═O)—O—).

R⁴ represents any of the alkyl, alkenyl, cycloalkyl, or cycloalkenylgroups described above for R¹. Preferably, R⁴ is a tert-butyl group.

In formula (1), R⁶ represents a fluorinated vinyl group having theformula

In formula (2), R⁷, R⁸, and R⁹ each independently represent a hydrogenor fluoro group provided that at least one of R⁷, R⁸, and R⁹ representsa fluoro group.

The fluorinated vinyl group can be a fluorovinyl, difluorovinyl, ortrifluorovinyl group.

The fluorovinyl group can be a 2-fluorovinyl group (—CH═CHF) or a2-fluorovinyl group (—CF═CH₂). In addition, the 2-fluorovinyl group canbe in a cis- or trans-configuration.

The difluorovinyl group can be a 2,2-difluorovinyl group (—CH═CF₂) or a1,2-difluorovinyl group (—CF═CHF). The 1,2-difluorovinyl group can havethe fluoro substituents in either a cis- or trans-configuration withrespect to each other.

The trifluorovinyl group corresponds to a 1,2,2-trifluorovinyl group(—CF═CF₂).

In a preferred embodiment, the taxoid compounds of the present inventionare represented by the formula:

In formula (3), R¹ and R² are independently as described above. Forexample, R¹ can be methyl, ethyl, methoxy, dimethylamino or cyclopropyland R² can be hydrogen, methyl, methoxy, chloro, fluoro or azido. Morepreferably, R¹ represents methyl, ethyl, methoxy, or cyclopropyl, and R²represents hydrogen, methoxy, or azido.

Some particularly preferred taxoid compounds of the present inventioninclude those listed in the table below. These taxoids have shownparticular potency for the inhibition of the growth of cancer cells asshown in the following table. The results were obtained according to themethods of Skehan et al (See Skehan et al., J. Nat. Cancer Inst., 82,1107 (1990)), as more fully described in the Examples. The resistancefactor (R/S) shown in the table is a measure of the degree of resistanceof a cell line against a taxoid compound. The resistance factor is aratio of the cytoxicity of a taxoid compound against a drug-resistantcell line (R) as compared to its cytoxicity against a drug-sensitivecell line (S).

Highly Potent Difluorovinyl-taxoids (IC₅₀ nM)

MCF7 MCF7-R Taxoid R X (breast) (breast) R/S Paclitaxel Me H 1.2 300 250SB-T-12851 Me H 0.099 0.95 9.6 SB-T-12852-1 cyclo-Pr MeO 0.092 0.48 5.2SB-T-12853-1 Et MeO 0.34 0.57 1.7 SB-T-12855-1 MeO MeO 0.078 0.50 6.4SB-T-12851-3 Me N₃ 0.092 0.34 3.7 SB-T-12852-3 cyclo-Pr N₃ 0.092 0.454.9 SB-T-12855-3 MeO N₃ 0.076 0.40 5.3

The fluorotaxoid compounds are either uncharged or in the form ofpharmaceutically acceptable salts. The term “pharmaceutically acceptablesalt” refers to a salt prepared from a suitable compound and, forexample, an acid or a base. The salt is acceptably non-toxic and hasacceptable pharmacokinetics. Such salts are formed by well knownprocedures.

Suitable acids for producing salts of the compounds of the inventioninclude mineral acids and organic acids. Some examples of mineral acidsinclude hydrochloric, hydriodic, hydrobromic, phosphoric,metaphosphoric, nitric and sulfuric acids. Some examples of organicacids include tartaric, acetic, citric, maleic, malic, benzoic,glycollic, gluconic, gulonic, succinic, arenesulfonic, e.g.p-toluenesulfonic acids, and the like.

Suitable bases for producing salts of the compounds of the inventioninclude inorganic bases and organic bases. Some examples of inorganicbases include ammonia and the hydroxides of lithium, sodium, potassium,magnesium and calcium. Some examples of organic bases include primary,secondary, and tertiary alkyl amines.

In another aspect, the invention is directed to a pharmaceuticalcomposition comprising a compound according to formula (1) or formula(3) and a pharmaceutically acceptable carrier. Compositions may, forexample, be pills, capsules, solutions, creams, etc.

In this specification, a pharmaceutically acceptable carrier isconsidered to be synonymous with a vehicle or an excipient as understoodby practitioners in the art. Examples of carriers include starch, milk,sugar, certain types of clay, gelatin, stearic acid or salts thereof,magnesium or calcium stearate, talc, vegetable fats or oils, gums andglycols.

The pharmaceutical formulation may also include one or more of thefollowing: a stabilizer, a surfactant, preferably a nonionic surfactant,and optionally a salt and/or a buffering agent.

The stabilizer can be, for example, an amino acid, e.g., glycine; or anoligosaccharide, e.g., sucrose, tetralose, lactose or a dextran.Alternatively, the stabilizer may be a sugar alcohol, e.g., mannitol; ora combination thereof.

The surfactant may be, for example, an ionic surfactant, such as apolyacrylate. Alternatively, the surfactant may be a nonionicsurfactant, such as a polyethylene glycol, polyoxyethylenepolyoxypropylene glycol, or polysorbate. Some examples of such non-ionicsurfactants include Tween 20, Tween 80, and Pluronic F-68 at from about0.001% (w/v) to about 10% (w/v).

The salt or buffering agent may be any salt or buffering agent, such as,for example, sodium chloride, sodium or potassium phosphates, citricacid, sodium or potassium citrates, or a mixture thereof. The bufferingagent is useful for maintaining the pH of the compounds of theinvention. The salt and/or buffering agent is also useful to maintainthe osmolality at a level suitable for administration to a mammal. Forexample, the salt or buffering agent can be present at a roughlyisotonic concentration of about 150 mM to about 300 mM.

The pharmaceutical compositions of the inventions may additionallycontain one or more conventional additives. Some examples of suchadditives include a solubilizer, such as, for example, glycerol; anantioxidant such as, for example, benzalkonium chloride (a mixture ofquaternary ammonium compounds, known as “quart”), benzyl alcohol,chloretone or chlorobutanol; an anaesthetic agent such as, for example,a morphine derivative; or an isotonic agent, etc. As a furtherprecaution against oxidation or other spoilage, the compounds of theinventions may be stored under nitrogen gas in vials sealed withimpermeable stoppers.

When aqueous suspensions are used for oral administration, emulsifyingand/or suspending agents are commonly added. In addition, coloring,sweetening and/or flavoring agents may be added to the oralcompositions.

Pharmaceutical compositions are preferably sterile. The pH of thesolutions can be suitably adjusted and buffered. For intravenous use,the total concentration of the solute(s) can be controlled in order torender the preparation isotonic.

Carrier compositions deemed to be suited for topical use include gels,salves, lotions, creams, ointments and the like. The compounds can alsobe incorporated with a support base or matrix or the like which can bedirectly applied to skin.

In another aspect, the invention is directed to inhibiting the growth ofcancer cells in a mammal in need thereof. In the method, an effectiveamount of a fluorotaxoid compound of the invention is administered to amammal.

The cancer cells can be any type of cancer treatable by the taxoidcompounds. For example, the cancer can be breast, ovary, lung, head,neck, colon, pancreatic, melanoma, brain, prostate, or renal cancer.

Any mammal in need thereof can be treated in accordance with the presentinvention. Mammals include, for example, humans, baboons, and otherprimates, as well as pet animals such as dogs and cats, laboratoryanimals such as rats and mice, and farm animals such as horses, sheep,and cows.

The method of the invention comprises administering an effective amountof a fluorotaxoid compound. An effective amount of the fluorotaxoid isany amount effective in treating cancer or for inhibiting the growth ofcancer cells in a mammal in need thereof.

The actual administered amount of the fluorotaxoid compound will varyaccording to various factors well known in the art, e.g., the type ofcancer, the particular fluorotaxoid being administered, the mode ofadministration, and the particular subject being treated. The amountrequired for effective treatment is governed by pharmacologicalstandards and by the discretion of medical practitioners in the art. Forexample, the effective amount can be determined during clinical andpre-clinical trials by methods familiar to physicians and clinicians.

The minimum amount of a fluorotaxoid administered to a human is thelowest amount capable of inhibiting the growth of cancer cells. Themaximum amount is the highest effective amount that does not causeundesirable or intolerable side effects. The minimum amount can be, forexample, 0.01, 0.05, or 0.1 milligrams per kilogram body weight per day.The maximum amount can be, for example, 10, 50, or 100 milligrams perkilogram body weight per day. Higher doses may be employed to treat thecancer to the extent patient tolerance permits.

The fluorotaxoid formulation may be administered alone or as an adjunctwith other conventional drugs for treating cancer. The adjunctive drugscan be, for example, chemotherapy drugs. Some examples of chemotherapydrugs include methotrexate (Abitrexate®), fluorouracil (Adrucil®),hydroxyurea (Hydreas), and mercaptopurine (Purinethol®).

The fluorotaxoid formulation may be administered by any suitable methodknown in the art. Some examples of suitable modes of administrationinclude oral, systemic, and topical administration.

For oral administration, liquid or solid oral formulations can be used,as known in the art. Some examples of formulations suitable for oraladministration include tablets, capsules, pills, troches, elixirs,suspensions, and syrups.

Systemic administration includes enteral or parenteral modes ofadministration, e.g., intravenous; intramuscular; subcutaneous; orintraperitoneal modes of administration. For example, the fluorotaxoidformulation may be administered by injection of a solution orsuspension; or intranasally, in the form of, for example, a nebulizer,liquid mist, or intranasal spray; or transdermally, in the form of, forexample, a patch; or rectally, in the form of, for example, asuppository; or intrabronchially, in the form of, for example, aninhaler spray.

Suitable carrier compositions for topical use include gels, salves,lotions, creams, ointments, and the like. The compounds can also beincorporated with a support base or matrix or the like which can bedirectly applied to skin.

The timing of the administration of the fluorotaxoid formulation mayalso be modified. For example, the formulation may be administeredintermittently or by controlled release. Controlled releaseadministration is a method of drug delivery to achieve a certain levelof the drug over a particular period of time. See, for example, U.S.Patent Publication No. 2004/0115261, incorporated herein by reference.

Examples have been set forth below for the purpose of illustration andto describe the best mode of the invention at the present time. However,the scope of this invention is not to be in any way limited by theexamples set forth herein.

EXAMPLES Example 1 Synthesis of 4-difluorovinyl β-Lactam

(3R,4S)-3-AcO-β-lactam was prepared through [2+2]ketene-iminecycloaddition, followed by enzymatic optical resolution of racemicβ-lactam (Scheme III-20).

The protecting group of the 3-acetoxy moiety of (3R,4S)-3-AcO-β-lactamwas changed to triisopropylsilyl (TIPS). The resulting(3R,4S)-1-PMP-3-TIPSO-4-(2-methyl-1-propenyl)azetidin-2-one II-(+) wassubjected to ozonolysis to give(3R,4S)-1-PMP-3-TIPSO-4-formylazetidin-2-one III-47 (Scheme III-21).

Enantiopure (3R,4S)-1-PMP-3-TIPSO-4-formylazetidin-2-one III-47 wastransformed to (3R,4S)-1-PMP-3-TIPSO-4-difluorovinyl-2-one III-48 usingCBr2F₂, hexamethylphosphorous triamide (HMPA), and Zn in THF (SchemeIII-22).

Finally the PMP group was removed using cerium ammonium nitrate (CAN) togive enantiopure (3R,4S)-3-TIPSO-4-difluorovinylazetidin-2-one III-49(+)followed by carbalkoxylation with di-t-butyl dicarbonate (Boc₂O) to givedesired (3R,4S)—N-Boc-3-TIPSO-4-difluorovinylazetidin-2-one III-50 inexcellent yields (Scheme III-24).

Example 2 Synthesis of C-3′ Difluorovinyl Second-Generation Taxoids

The synthesis of baccatin core was performed using literature methodsstarting from 10-DAB, yielding III-41 or III-43 in high yields (SchemeIII-25).

The ring-opening coupling of β-lactams with modified baccatins wascarried out at −40° C. in THF using LiHMDS. The subsequent removal ofthe silyl protecting groups by HF/pyridine gave the corresponding newdifluorovinyl-taxoids III-51 in fairly good overall yields (SchemeIII-26).

Example 31-(4-Methoxyphenyl)-3-triisopropylsilanyloxy-4-(2,2-difluorovinyl)azetidin-2-one(III-48)

To a solution of dibromodifluoromethane (1.97 mL, 12.79 mmol) in THF (85mL) were added hexamethylphosphorous triamide (4.79 mL, 25.56 mmol) andZn (1.67 g, 25.56 mmol) at −78° C. The mixture was allowed to warmslowly to −10° C. The mixture was stirred for additional 30 min at −10°C. and ether was added to the reaction mixture. The ether layer wasdecanted and the residue was washed with dichloromethane and water. Thecombined organic layers were washed with saturated copper sulfatesolution until the blue color stayed, and dried over MgSO₄. The filtratewas concentrated under reduced pressure to give yellow oil. Crudematerial was purified by flash chromatography on silica gel to yieldIII-48 (688 mg, 68%): ¹H NMR (CDCl₃, 300 MHz): α 1.08-1.15 (21H, m),3.79 (3H, s), 4.54 (1H, ddd, J=1.5, 6.3, 16.5 Hz), 4.83 (1H, m), 5.14(1H, d, J=5.1 Hz), 6.87 (2H, d, J=9.0 Hz), 7.32 (2H, d, J=9.0 Hz); ¹³CNMR (CDCl₃, 75.5 MHz): α 12.1, 17.9, 54.1 (d, J=8.5 Hz), 55.8, 75.8 (dd,J=5.0, 22.1 Hz), 76.9, 77.4, 114.8, 118.6, 130.9, 156.7, 164.9; ¹⁹F NMR(282 MHz, CDCl₃): δ −80.80 (d, 1F, J=32.7 Hz), −86.34 (dd, 1F, J=2.8 Hz,J=28.2). LRMS (FAB+, m/z): Calcd. for C₂₁H₃₁F₂NO₃Si.H+, 412.2114; Found,412.2127.

Example 4 3-Triisopropylsiloxy-4-(2,2-difluorovinyl)azetidin-2-one(III-49)

To a solution of N-PMP-β-lactam (688 mg, 1.67 mmol) in acetonitrile (50mL) and water (10 mL), was added dropwise a solution of ceric ammoniumnitrate (3.74 g, 6.69 mmol) in water (40 mL). The reaction mixture wasstirred for 2 h. Work up with water and saturated Na₂SO₃ solution. Theaqueous layer was extracted with EtOAc, and the combined organic layerwas washed with water, dried over MgSO₄ and concentrated. The crudeproduct was purified on a silica gel column to yield the β-lactam III-49as a pale yellow oil (469 mg, 92% yield): ¹H NMR (CDCl₃, 400 MHz): α1.03-1.18 (21H, m), 4.44-4.54 (2H, m), 5.04 (1H, dd, J=1.6, 2.4 Hz),6.59 (1H, bs); ¹³C NMR (CDCl₃, 100 MHz): α 12.1, 17.8 (d, J=4.6 Hz),50.4 (d, J=7.6 Hz), 77.1 (dd, J=15.9, 23.5 Hz), 79.3, 157.6 (t, J=289.9Hz), 169.4; ¹⁹F NMR (282 MHz, CDCl₃): δ −82.33 (d, 1F, J=34.7 Hz),−87.50 (dd, 1F, J=9.3, 25.7 Hz).

Example 51-(tert-Butoxycarbonyl)-3-triisopropylsiloxy-4-(2,2-difluorovinyl)azetidin-2-one(III-50)

To a solution of 4-(2,2-difluorovinyl)-β-lactam III-49 (469 mg, 1.54mmol), triethylamine (0.75 mL, 4.62 mmol), and DMAP (43 mg, 0.35 mmol)in CH₂Cl₂ (9 mL), was added Boc₂O (398 mg, 1.77 mmol) at roomtemperature. The reaction mixture was stirred for 18 hours and quenchedwith water. The reaction mixture was diluted with ethylacetate (EtOAc)and the organic layer was washed with brine, dried over MgSO₄, andconcentrated under reduced pressure. Crude material was purified byflash chromatography on silica gel to give1-Boc-4-(2,2-difluorovinyl)-β-lactam III-50 as yellow oil (599 mg, 96%yield): [α]_(D) ²⁰ +24.17 (c 14.4, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): α1.04-1.17 (21H, m), 1.49 (9H, s), 4.49 (1H, ddd, J=1.6, 13.8, 23.7 Hz),4.75 (1H, dddd, J=0.9, 2.4, 5.1, 9.0 Hz), 5.04 (1H, d, J=5.7 Hz), 6.59(1H, bs); ¹³C NMR (CDCl₃, 100 MHz): α 12.0, 17.8 (d, J=5.3 Hz), 28.2,53.6 (d, J=8.4 Hz), 74.5 (dd, J=10.6, 26.5 Hz), 77.2, 83.9, 147.9, 158.5(t, J=292.2 Hz), 165.3; ¹⁹F NMR (282 MHz, CDCl₃): δ −81.20 (d, 1F,J=31.0 Hz), −85.83 (dd, 1F, J=5.6 Hz, J=29.3). HRMS (FAB+, m/z): Calcd.For C₁₉H₃₃F₂NO₄Si.Na+, 428.2039; Found, 428.2050.

Example 6 10-Acetyl-3′-dephenyl-3′-(2,2-difluorovinyl)docetaxel,SB-T-12851 (III-51a)

Yield 83%; white solid; mp 155-160° C.; [α]D²⁰ −74.83 (c 2.86, CHCl₃);¹H NMR (CDCl₃, 400 MHz): α 1.15 (3H, s, C-16), 1.25 (3H, m, C-17), 1.30(9H, s, Boc), 1.68 (3H, s, H-19), 1.75 (bs, 1H, OH), 1.88 (4H, m, H-6b,H-18), 2.24 (3H, s, 10-OAc), 2.33 (2H, m, H-14), 2.39 (3H, s, 4-OAc),2.49 (1H, d, J=3.6 Hz, OH), 2.55 (1H, ddd, J=6.4, 9.6, 14.8 Hz, H-6a),3.52 (1H, d, J=5.6 Hz, OH), 3.81 (1H, d, J=7.2 Hz, H-3), 4.17 (1H, d,J=8.4 Hz, H-20b), 4.28 (1H, s, J=2.8 Hz, H-2′), 4.31 (1H, d, J=8.4 Hz,H-20a), 4.44 (1H, m, H-7), 4.58 (1H, ddd, J=1.2, 9.6, 24.8 Hz,H-3′-vinyl), 4.87 (1H, t, J=8.8 Hz, H-3′), 4.96 (2H, d, J=9.6, H-5,NH-3′), 5.66 (1H, d, J=7.2 Hz, H-2), 6.24 (1H, t, J=8.8 Hz, H-13), 6.30(1H, s, H-10), 7.49 (2H, t, J=7.6 Hz), 7.61 (1H, t, J=7.2 Hz), 8.11 (2H,d, J=7.6 Hz); ₁₃C NMR (CDCl₃, 100 MHz) α 9.8, 14.4, 15.1, 21.1, 22.1,22.5, 26.9, 28.3, 35.7 (d, J=13.7 Hz), 43.5, 45.7, 48.2, 58.8, 72.4,72.9, 75.8, 76.7, 79.3, 80.7, 81.3, 84.6, 128.9, 129.3, 130.4, 133.4,133.9, 142.4, 155.1, 156.7, 158.0, 167.3, 170.5, 171.5, 172.7, 203.9;₁₉F NMR, (CDCl₃, 282 MHz) δ −84.29 (1F, dd, J=25.7, 36.4 Hz), −86.22(1F, dd, J=34.7 Hz); HRMS (FAB+, m/z): Calcd. for C₄₁H₅₁F₂NO₁₅.H+,836.3300; Found, 836.3278.

Example 73′-dephenyl-3′-(2,2-difluorovinyl)-10-cyclopropanecarbonyl-docetaxel,SB-T-12852 (III-51b)

Yield 88%; white solid; mp 171-177° C.; [α]_(D) ²⁰ −73.71 (c 5.44,CHCl₃); ¹H NMR (CDCl₃, 400 MHz): α 0.98 (2H, m, CH₂-c-Pr), 1.13 (2H, m,CH₂-c-Pr), 1.15 (3H, s, C-16), 1.26 (3H, m, C-17), 1.30 (9H, s, Boc),1.66 (3H, s, H-19), 1.78 (2H, m, OH, CH-c-Pr), 1.87 (4H, m, H-6b, H-18),2.31 (2H, m, H-14), 2.38 (3H, s, 4-OAc), 2.53 (1H, ddd, J=6.8, 10.0,15.2 Hz, H-6a), 2.59 (1H, d, J=3.2 Hz, OH), 3.57 (1H, bs, OH), 3.80 (1H,d, J=6.8 Hz, H-3), 4.17 (1H, d, J=8.4 Hz, H-20b), 4.28 (2H, m, H-2′,H-20a), 4.40 (1H, m, H-7), 4.58 (1H, ddd, J=1.6, 9.6, 24.8 Hz,H-3′-vinyl), 4.87 (1H, t, J=8.8 Hz, H-3′), 4.97 (2H, m, H-5, NH′), 5.66(1H, d, J=7.2 Hz, H-2), 6.24 (1H, t, J=8.0 Hz, H-13), 6.29 (1H, s,H-10), 7.49 (2H, t, J=7.6 Hz), 7.60 (1H, t, J=7.6 Hz), 8.11 (2H, d,J=7.2 Hz); ¹³C NMR (CDCl₃, 100 MHz) α 9.4, 9.6, 9.8, 13.2, 22.5, 27.0,28.3, 35.7, (d, J=5.3 Hz), 43.5, 45.9, 48.2, 58.8, 72.4, 72.9, 73.3,75.3, 75.6, 76.6, 79.3, 80.7, 81.3, 84.7, 128.9, 129.3, 130.4, 133.4,133.9, 142.4, 155.1, 156.7, 167.3, 170.5, 172.6, 175.3, 204.0; ¹⁹F NMR,(CDCl₃, 282 MHz) δ −84.32 (1F, dd, J=25.4, 36.4 Hz), −86.30 (1F, dd,J=36.7 Hz); HRMS (FAB+, m/z): Calcd. for C₄₃H₅₃F₂NO₁₅.H+, 862.3456;Found, 862.3445.

Example 8 3′-Dephenyl-3′-(2,2-difluorovinyl)-10-propanoyl-docetaxel,SB-T-12853 (III-51c)

Yield 64%; white solid; mp 175-181° C.; [α]_(D) ²⁰ −82.83 (c 5.01,CHCl₃); ¹H NMR (CDCl₃, 400 MHz): α 1.14 (3H, s, H-16), 1.24 (6H, m,H-17, H-10-CH₃), 1.30 (9H, s, Boc), 1.67 (3H, s, H-19), 1.78 (1H, m,OH), 1.87 (4H, m, H-6b, H-18), 2.31 (2H, m, H-14), 2.38 (3H, s, 4-OAc),2.53 (4H, m, H-6a, H-10, CH₂, OH), 3.55 (1H, bs, OH), 3.81 (1H, d, J=6.8Hz, H-3), 4.17 (1H, d, J=8.4 Hz, H-20b), 4.29 (2H, m, H-2′, H-20a), 4.39(1H, m, H-7), 4.56 (1H, ddd, J=1.6, 9.6, 24.8 Hz, H-3′-vinyl), 4.86 (1H,t, J=8.8 Hz, H-3′), 4.96 (2H, m, H-5, NH′), 5.66 (1H, d, J=7.2 Hz, H-2),6.25 (1H, t, J=8.4 Hz, H-13), 6.30 (1H, s, H-10), 7.49 (2H, t, J=7.6Hz), 7.60 (1H, t, J=7.2 Hz), 8.11 (2H, d, J=7.2 Hz); ¹³C NMR (CDCl₃, 100MHz) α 9.2, 9.8, 15.1, 22.1, 22.5, 26.9, 27.8, 28.4, 35.7 (d, J=12.9Hz), 43.5, 45.9, 48.2, 58.8, 72.2, 72.4, 72.9, 73.3, 75.3, 75.6, 76.6,77.4, 79.3, 80.7, 81.3, 84.6, 128.9, 129.3, 130.4, 133.5, 133.9, 142.2,155.1, 156.7, 167.3, 170.5, 172.6, 174.8, 203.9; ¹⁹F NMR, (CDCl₃, 282MHz) δ −84.31 (1F, dd, J=23.7, 34.7 Hz), −86.23 (1F, dd, J=36.4 Hz);HRMS (FAB+, m/z): Calcd. For C₄₂H₅₃F₂NO₁₅.H+, 850.3456; Found 850.3450.

Example 93′-Dephenyl-3′-(2,2-difluorovinyl)-10-dimethylcarbamoyldocetaxel,SB-T-12854 (III-51d)

Yield 84%; white solid; mp 166-170° C.; [α]_(D) ²⁰ −70.48 (c 6.3,CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ1.15 (3H, s, H-16), 1.25 (3H, m,H-17), 1.30 (9H, s, Boc), 1.67 (3H, s, H-19), 1.84 (1H, m, OH), 1.89(4H, m, H-6b, H-18), 2.31 (2H, m, H-14), 2.38 (3H, s, 4-OAc), 2.53 (1H,ddd, J=6.8, 9.6, 15.2 Hz, H-6a), 3.64 (1H, d, J=5.6 Hz, OH), 3.80 (1H,d, J=6.8 Hz, H-3), 4.17 (1H, d, J=8.4 Hz, H-20b), 4.29 (2H, m, H-2′,H-20a), 4.44 (1H, m, H-7), 4.57 (1H, dd, J=10.0, 25.2 Hz, H-3′-vinyl),4.86 (1H, t, J=8.8 Hz, H-3′), 4.97 (1H, d, J=9.2 Hz, NH-3′), 5.02 (1H,d, J=9.6 Hz, H-5), 5.66 (1H, d, J=7.2 Hz, H-2), 6.24 (2H, m, Hz, H-13,H-10), 7.49 (2H, t, J=7.6 Hz), 7.59 (1H, t, J=7.2 Hz), 8.10 (2H, d,J=7.6 Hz); ¹³C NMR (CDCl₃, 100 MHz) α 9.6, 15.1, 22.1, 22.5, 27.1, 28.3,35.6 (d, J=12.1 Hz), 36.3, 36.8, 43.5, 45.8, 48.2, 58.7, 72.6, 72.9,73.3, 75.4, 76.3, 76.7, 77.4, 79.4, 80.6, 81.3, 84.6, 128.9, 129.4,130.4, 133.7, 133.9, 142.7, 155.1, 156.3, 156.5, 167.3, 170.4, 171.3,203.9; ¹⁹F NMR, (CDCl₃, 282 MHz) δ −84.31 (1F, dd, J=25.7, 37.2 Hz),−86.23 (1F, dd, J=36.4 Hz); HRMS (FAB+, m/z): Calcd. ForC₄₂H₅₄F₂N₂O₁₅.H+, 865.3565; Found 865.3562.

Example 103′-Dephenyl-3′-(2,2-difluorovinyl)-10-methoxycarbonyldocetaxel,SB-T-12855 (III-51e)

Yield 90%; white solid; mp 144-148° C.; [α]_(D) ²⁰ −77.06 (c 6.8,CHCl₃); ₁H NMR (CDCl₃, 400 MHz): δ1.15 (3H, s, H-16), 1.24 (3H, m,H-17), 1.29 (9H, s, Boc), 1.68 (3H, s, H-19), 1.78 (1H, m, OH), 1.88(1H, m, H-6b), 1.91 (3H, s, H-18), 2.31 (2H, m, H-14), 2.39 (3H, s,4-OAc), 2.53 (2H, m, H-6a, OH), 3.55 (1H, d, J=5.6 Hz, OH), 3.78 (1H, d,J=7.2 Hz, H-3), 3.86 (3H, s, H-10-MeO), 4.17 (1H, d, J=8.4 Hz, H-20b),4.29 (2H, m, H-2′, H-20a), 4.38 (1H, m, H-7), 4.57 (1H, ddd, J=1.6, 9.6,24.8 Hz, H-3′-vinyl), 4.86 (1H, t, J=8.8 Hz, H-3′), 4.96 (2H, m, H-5,NH′), 5.66 (1H, d, J=6.8 Hz, H-2), 6.11 (1H, s, H-10), 6.23 (2H, t,J=8.0 Hz, H-13), 7.49 (2H, t, J=7.6 Hz), 7.60 (1H, t, J=7.2 Hz), 8.10(2H, d, J=7.2 Hz); ¹³C NMR (CDCl₃, 100 MHz) α 9.7, 15.2, 22.1, 22.5,26.8, 28.3, 35.8 (d, J=23.5 Hz), 43.4, 45.9, 48.2, 55.8, 58.8, 72.1,72.3, 72.8, 73.3, 75.2, 76.7, 77.4, 78.4, 79.2, 80.7, 81.2, 84.6, 128.9,129.3, 130.4, 133.0, 133.9, 143.2, 155.1, 155.9, 156.5, 167.3, 170.6,172.3, 204.1; ¹⁹F NMR, (CDCl₃, 282 MHz) δ −84.30 (1F, dd, J=23.7, 34.7Hz), −86.22 (1F, dd, J=34.7 Hz); HRMS (FAB+, m/z): Calcd. forC₄₁H₅₁F₂NO₁₆—H+, 852.3249; Found 852.3227.

Example 113′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-fluorobenzoyl)-10-acetyldocetaxel,SB-T-12851-2 (III-51f)

Yield 72%; white solid; [α]_(D) ²⁰ −73.29 (c, 7.0 CHCl₃); ¹H NMR (CDCl₃,400 MHz): α 1.15 (3H, s, C-16), 1.26 (3H, m, C-17), 1.31 (9H, s, Boc),1.68 (4H, s, H-19, OH), 1.89 (4H, m, H-6b, H-18), 2.24 (3H, s, 10-OAc),2.33 (2H, m, H-14), 2.39 (3H, s, 4-OAc), 2.47 (1H, bs, OH), 2.56 (1H,ddd, J=7.0, 9.5, 15.0 Hz, H-6a), 3.46 (1H, bs, OH), 3.82 (1H, d, J=7.0Hz, H-3), 4.16 (1H, d, J=8.5 Hz, H-20b), 4.28 (1H, s, H-2′), 4.31 (1H,d, J=8.5 Hz, H-20a), 4.42 (1H, dd, J=6.5, 11.0 Hz, H-7), 4.58 (1H, ddd,J=1.0, 9.0, 26.0 Hz, H-3′vinyl), 4.90 (2H, m, H-3′, NH-3′), 4.97 (1H,dd, J=2.0, 9.0, H-5), 5.64 (1H, d, J=7.0 Hz, H-2), 6.23 (1H, t, J=8.0Hz, H-13), 6.30 (1H, s, H-10), 7.31 (1H, dt, J=2.0, 8.0 Hz), 7.49 (1H,ddd, J=6.0, 8.5, 13.5 Hz), 7.80 (1H, d, J=9.0 Hz), 7.91 (1H, d, J=7.5Hz); ¹³C NMR (CDCl₃, 100 MHz) α 9.5, 14.8, 20.8, 21.8, 22.2, 26.7, 28.1,35.5 (d, J=11.8 Hz), 43.2, 45.6, 58.5, 72.1, 72.5, 73.1, 75.5, 76.3,79.1, 80.4, 80.9, 84.4, 117.0 (J=23.2 Hz), 120.8 (J=21.1 Hz), 125.9,130.4 (J=7.8 Hz), 131.2 (J=7.4 Hz), 132.9, 142.2, 154.9, 156.7, 160.9,164.2, 165.9, 170.2, 171.2, 203.5; ¹⁹F NMR, (CDCl₃, 282 MHz) δ −84.23(1F, dd, J=25.7, 34.7 Hz), −86.21 (1F, dd, J=36.7 Hz), −111.7 (1F, dd,J=9.3, 14.6 Hz); HRMS (FAB+, m/z): Calcd. for C₄₁H₅₀F₃NO₁₅.H+, 854.3205;Found, 854.3207.

Example 123′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-fluorobenzoyl)-10-cyclopropanecarbonyldocetaxel,SB-T-12852-2 (III-51g)

Yield 78%; white solid; [α]_(D) ²⁰ −77.04 (c 7.1, CHCl₃); ¹H NMR (CDCl₃,500 MHz): α 0.99 (2H, m, CH₂-c-Pr), 1.12 (2H, m, CH₂-c-Pr), 1.15 (3H, s,C-16), 1.26 (3H, m, C-17), 1.30 (9H, s, Boc), 1.66 (3H, s, H-19), 1.77(2H, m, OH, CH-c-Pr), 1.86 (1H, m, H-6b), 1.87 (3H, s, H-18), 2.33 (2H,m, H-14), 2.39 (3H, s, 4-OAc), 2.53 (1H, ddd, J=7.0, 9.5, 15.5 Hz,H-6a), 2.61 (1H, bs, OH), 3.55 (1H, bs, OH), 3.80 (1H, d, J=7.0 Hz,H-3), 4.17 (1H, d, J=8.0 Hz, H-20b), 4.28 (1H, s, H-2′), 4.29 (1H, d,J=8.0 Hz, H-20a), 4.40 (1H, dd, J=7.0, 10.5 Hz, H-7), 4.58 (1H, dd,J=8.5, 23.5 Hz, H-3′ vinyl), 4.86 (1H, m, H-3′), 4.97 (2H, m, H-5, NH′),5.63 (1H, d, J=7.0 Hz, H-7), 6.24 (1H, t, J=9.5 Hz, H-13), 6.29 (1H, s,H-10), 7.49 (2H, dt, J=2.5, 8.5 Hz), 7.60 (1H, ddd, J=6.0, 8.0, 13.5Hz), 7.78 (1H, d, J=9.5 Hz), 7.90 (1H, d, J=7.5 Hz); ¹³C NMR (CDCl₃, 125MHz) α 9.2, 9.5, 13.0, 14.7, 21.9, 22.2, 26.7, 28.1, 35.5, (d, J=5.4Hz), 43.2, 45.6, 48.0, 58.5, 72.1, 72.5, 73.1, 75.3, 75.5, 76.3, 79.1,80.4, 80.9, 84.4, 117.0 (d, J=23.8 Hz), 120.8 (d, J=21.2 Hz), 125.9,130.4 (d, J=7.7 Hz), 131.3 (d, J=7.7 Hz), 133.0, 142.2, 154.8, 160.9,164.2, 165.8, 170.2, 175.1, 203.7; ¹⁹F NMR, (CDCl₃, 282 MHz) δ −84.22(1F, dd, J=23.7, 36.7 Hz), −86.20 (1F, d, J=34.7 Hz), −111.72 (1F, dd,J=9.3, 14.6 Hz); HRMS (FAB+, m/z): Calcd. for C₄₃H₅₂F₃NO₁₅.H+, 880.3362;Found, 880.3346.

Example 133′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-fluorobenzoyl)-10-propanoyldocetaxel,SB-T-12853-2 (III-51h)

Yield 71%; white solid; [α]_(D) ²⁰ −71.57 (c 8.3, CHCl₃); ₁H NMR (CDCl₃,500 MHz): α 1.14 (3H, s, H-16), 1.24 (6H, m, H-17, H-10-CH₃), 1.31 (9H,s, Boc), 1.67 (3H, s, H-19), 1.72 (1H, bs, OH), 1.88 (4H, m, H-6b,H-18), 2.32 (2H, m, H-14), 2.39 (3H, s, 4-OAc), 2.53 (3H, m, H-6a, H-10,CH₂), 3.51 (1H, bs, OH), 3.82 (1H, d, J=7.0 Hz, H-3), 4.16 (1H, d, J=8.5Hz, H-20b), 4.28 (1H, d, J=1.5 Hz, H-2′), 4.30 (1H, d, J=8.5 Hz, H-20a),4.42 (1H, dd, J=6.5, 10.5 Hz, H-7), 4.58 (1H, ddd, J=1.5, 9.0, 24.5 Hz,H-3′), 4.87 (1H, m, H-3′), 4.96 (2H, m, H-5, NH′-3′), 5.64 (1H, d, J=6.5Hz, H-2), 6.23 (1H, t, J=8.0 Hz, H-13), 6.31 (1H, s, H-10), 7.31 (1H,dt, J=2.0, 7.0 Hz), 7.48 (1H, ddd, J=5.5, 7.5, 13.0 Hz), 7.80 (1H, d,J=8.5 Hz), 7.91 (1H, d, J=7.5 Hz); ¹³C NMR (CDCl₃, 125 MHz) α 8.9, 9.5,14.8, 21.9, 22.2, 26.7, 27.5, 28.1, 35.5 (d, J=10.3 Hz), 43.2, 45.6,58.5, 72.1, 72.5, 73.1, 75.3, 75.4, 76.3, 79.1, 80.9, 84.4, 116.9 (d,J=23.8 Hz), 120.8 (d, J=21.2 Hz), 125.9, 130.4 (d, J=7.5 Hz), 131.3 (d,J=7.4 Hz), 133.0, 142.1, 154.6, 160.9, 164.2, 165.8, 170.2, 174.6,203.6; ¹⁹F NMR, (CDCl₃, 282 MHz) δ −84.24 (1F, dd, J=23.9, 34.9 Hz),−86.22 (1F, d, J=36.4 Hz); HRMS (FAB+, m/z): Calcd. for C₄₂H₅₂F₃NO₁₅.H+,868.3362; Found 868.3352.

Example 143′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-fluorobenzoyl)-10-dimethylcarbamoyldocetaxel,SB-T-12854-2 (III-51i)

Yield 71%; white solid; [α]_(D) ²⁰ −85.33 (c 1.5, CHCl₃); ¹H NMR (CDCl₃,500 MHz): α 1.16 (3H, s, H-16), 1.26 (3H, m, H-17), 1.31 (9H, s, Boc),1.60 (1H, OH), 1.67 (3H, s, H-19), 1.84 (1H, m, OH), 1.89 (1H, m, H-6b),1.91 (3H, s, H-18), 2.33 (2H, m, H-14), 2.40 (3H, s, 4-OAc), 2.55 (1H,ddd, J=6.0, 9.5, 14.5 Hz, H-6a), 2.97 (3H, s, NMe), 3.05 (3H, s, N-Me),3.40 (1H, s, OH), 3.82 (1H, d, J=7.0 Hz, H-3), 4.17 (1H, d, J=7.5 Hz,H-20b), 4.29 (1H, s, H-2′), 4.31 (1H, d, J=7.5 Hz, H-20a), 4.45 (1H, dd,J=6.0, 10.5 Hz, H-7), 4.58 (1H, m, H-3′vinyl), 4.87 (2H, bs, H-3′,NH-3′), 4.99 (1H, d, J=8.0 Hz, H-5), 5.64 (1H, d, J=7.0 Hz, H-2), 6.26(2H, m, Hz, H-13, H-10), 7.32 (2H, dt, J=2.0, 8.0 Hz), 7.49 (1H, ddd,J=6.0, 8.5, 13.5 Hz), 7.81 (1H, d, J=9.5 Hz), 7.92 (1H, d, J=8.0 Hz);¹³C NMR (CDCl₃, 125 MHz) α 9.3, 14.7, 22.3, 26.9, 28.1, 35.4 (d, J=6.0Hz), 36.0, 36.6, 43.2, 45.5, 58.5, 72.4, 72.7, 73.1, 75.6, 76.1, 76.4,77.2, 79.3, 80.4, 81.1, 84.6, 110.7 (d, J=15.1 Hz), 120.8 (d, J=21.2Hz), 125.9, 130.4 (d, J=7.7 Hz), 131.3 (d, J=7.5 Hz), 133.9, 142.7,155.1, 157.4, 161.2, 164.1, 166.1, 170.2, 172.3, 205.5; ¹⁹F NMR, (CDCl₃,282 MHz) δ −84.13 (1F, dd, J=25.4, 36.4 Hz), −86.13 (1F, d, J=36.6 Hz),−111.73 (1F, dd, J=9.3, 14.6 Hz); HRMS (FAB+, m/z): Calcd. forC₄₂H₅₃F₃N₂O₁₅.H⁺, 883.3471; Found 883.3433.

Example 153′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-fluorobenzoyl)-10-methoxycarbonyldocetaxel,SB-T-12855-2 (III-51j)

Yield 72%; white solid; [α]_(D) ²⁰ −70.31 (c 6.5, CHCl₃); ¹H NMR (CDCl₃,500 MHz): α 1.15 (3H, s, H-16), 1.25 (3H, m, H-17), 1.29 (9H, s, Boc),1.65 (1H, bs, OH), 1.69 (3H, s, H-19), 1.88 (1H, m, H-6b), 1.92 (3H, s,H-18), 2.31 (2H, m, H-14), 2.39 (3H, s, 4-OAc), 2.46 (1H, bs, OH), 2.57(1H, ddd, J=6.0, 9.0, 15 Hz, H-6a), 3.48 (1H, bs, OH), 3.79 (1H, d,J=7.5 Hz, H-3), 3.87 (3H, s, H-10-MeO), 4.16 (1H, d, J=8.5 Hz, H-20b),4.28 (1H, s, H-2′), 4.31 (1H, d, J=8.5 Hz, H-20a), 4.39 (1H, dd, J=7.0,10.5 Hz, H-7), 4.58 (1H, dd, J=9.0, 24.5 Hz, H-3′ vinyl), 4.87-4.94 (2H,m, H-3′, NH-3′), 4.97 (1H, d, J=8.0 Hz, H-5), 5.65 (1H, d, J=7.0 Hz,H-2), 6.12 (1H, s, H-10), 6.23 (2H, t, J=9.0 Hz, H-13), 7.31 (1H, dt,J=2.5, 8.5 Hz), 7.49 (1H, ddd, J=5.0, 7.5, 13.5 Hz,), 7.79 (1H, d, J=8.5Hz), 7.91 (1H, d, J=8.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 9.4, 14.9, 21.8,22.2, 26.6, 28.1, 35.3, 35.6, 43.1, 45.6, 47.9, 55.6, 58.5, 72.1, 72.5,73.1, 75.4, 76.3, 78.2, 79.2, 80.5, 81.0, 84.6, 117.1 (d, J=23.5 Hz),120.8 (d, J=21.4 Hz), 126.0, 130.4 (d, J=8.0 Hz), 131.3 (d, J=7.5 Hz),132.7, 143.1, 154.9, 155.7, 160.9, 164.2, 165.9, 170.3, 203.8; ¹⁹F NMR,(CDCl₃, 282 MHz) δ −84.15 (1F, dd, J=25.4, 36.4 Hz), −86.17 (1F, d,J=36.7 Hz), −111.71 (1F, dd, J=9.3, 14.6 Hz); HRMS (FAB⁺, m/z): Calcd.for C₄₁H₅₀F₃NO₁₆.H⁺, 870.3154; Found 870.3146.

Example 163′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-chlorobenzoyl)-10-acetyldocetaxel,SB-T-12851-4 (III-51k)

Yield 57%; white solid; mp ° C.; [α]_(D) ²⁰ −72.93 (c 4.1, CHCl3); ¹HNMR (CDCl₃, 500 MHz): α 1.14 (3H, s, C-16), 1.25 (3H, m, C-17), 1.31(9H, s, Boc), 1.67 (3H, s, H-19), 1.73 (1H, s, OH), 1.89 (4H, m, H-6b,H-18), 2.24 (3H, s, 10-OAc), 2.33 (2H, d, J=8.5 Hz, H-14), 2.39 (3H, s,4-OAc), 2.51 (1H, d, J=3.5 Hz, OH), 2.55 (1H, ddd, J=6.5, 9.0, 15.0 Hz,H-6a), 3.51 (1H, bs, OH), 3.81 (1H, d, J=7.5 Hz, H-3), 4.15 (1H, d,J=8.5 Hz, H-20b), 4.29 (2H, m, H-2′, H-20a), 4.41 (1H, dd, J=6.5, 11.0Hz, H-7), 4.58 (1H, ddd, J=1.0, 10.0, 24.5 Hz, H-3′vinyl), 4.86 (1H, m,H-3′), 4.93 (1H, d, J=9.0 Hz, NH-3′), 4.98 (1H, d, J=7.5, H-5), 5.62(1H, d, J=7.5 Hz, H-2), 6.21 (1H, t, J=9.5 Hz, H-13), 6.30 (1H, s,H-10), 7.45 (1H, t, J=7.5 Hz), 7.58 (1H, dd, J=1.5, 8.5 Hz), 8.00 (1H,d, J=7.5 Hz), 8.12 (1H, s); ¹³C NMR (CDCl3, 125 MHz) α 9.5, 14.8, 20.8,21.8, 22.1, 26.7, 28.1, 35.4 (d, J=16.7 Hz), 43.1, 45.6, 58.5, 72.1,72.5, 73.1, 75.5, 76.3, 79.2, 80.4, 80.9, 84.3, 128.2, 130.0, 130.3,130.9, 132.9, 134.8, 142.2, 154.8, 165.7, 170.2, 171.2, 203.5; ¹⁹F NMR,(CDCl₃, 282 MHz) δ −84.15 (1F, dd, J=25.7, 36.7 Hz), −86.12 (1F, dd,J=36.7 Hz); HRMS (FAB+, m/z): Calcd. for C₄₁H₅₀ClF₂NO₁₅.H⁺, 870.2910;Found, 870.2891.

Example 173′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-chlorobenzoyl)-10-cyclopropanecarbonyldocetaxel,SB-T-12852-4 (III-51l)

Yield 73%; white solid; mp ° C.; [α]_(D) ²⁰ −78.97 (c 5.8, CHCl₃); ¹HNMR (CDCl₃, 400 MHz): α 1.02 (2H, m, CH₂-c-Pr), 1.15 (2H, m, CH₂-c-Pr),1.16 (3H, s, C-16), 1.28 (3H, m, C-17), 1.32 (9H, s, Boc), 1.68 (3H, s,H-19), 1.70 (1H, bs, OH), 1.80 (1H, m, CH-c-Pr), 1.86-1.89 (1H, m,H-6b), 1.89 (3H, s, H-18), 2.33 (2H, m, H-14), 2.41 (3H, s, 4-OAc), 2.56(1H, ddd, J=7.0, 9.0, 15.0 Hz, H-6a), 2.59 (1H, bs, OH), 3.51 (1H, bs,OH), 3.82 (1H, d, J=7.0 Hz, H-3), 4.16 (1H, d, J=8.5 Hz, H-20b), 4.29(1H, s, H-2′), 4.31 (1H, d, J=8.5 Hz, H-20a), 4.41 (1H, dd, J=7.0, 10.5Hz, H-7), 4.59 (1H, dd, J=9.0, 25.0 Hz, H-3′ vinyl), 4.89 (1H, m, H-3′),4.98 (2H, m, H-5, NH′), 5.63 (1H, d, J=7.0 Hz, H-7), 6.24 (1H, t, J=9.0Hz, H-13), 6.31 (1H, s, H-10), 7.46 (2H, t, J=8.5 Hz), 7.60 (1H, dd,J=1.0, 7.0 Hz), 8.01 (1H, d, J=7.5 Hz), 8.13 (1H, s); ¹³C NMR (CDCl₃,100 MHz) α 9.2, 9.4, 13.0, 14.9, 21.9, 22.2, 26.7, 28.1, 35.4, (d, J=7.9Hz), 43.2, 45.6, 48.0, 58.5, 72.1, 72.6, 73.1, 75.3, 75.5, 76.3, 77.2,79.2, 80.4, 81.0, 84.4, 128.3, 130.0, 130.3, 130.9, 133.0, 133.7, 134.8,142.3, 154.8, 165.7, 170.2, 175.1, 203.7; ¹⁹F NMR (CDCl_(3,) 282 MHz) δ−84.15 (1F, dd, J=25.7, 34.7 Hz), −86.16 (1F, d, J=36.7 Hz); HRMS (FAB⁺,m/z): Calcd. for C₄₃H₅₂ClF₂NO₁₅—H⁺, 896.3066; Found, 896.3036.

Example 183′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-chlorobenzoyl)-10-propanoyldocetaxel,SB-T-12853-4 (III-51m)

Yield 72%; white solid; [α]_(D) ²⁰ −76.73 (c 4.9, CHCl₃); ¹H NMR (CDCl₃,500 MHz): α 1.14 (3H, s, H-16), 1.22-1.25 (6H, m, H-17, H-10-CH₃), 1.31(9H, s, Boc), 1.67 (3H, s, H-19), 1.71 (1H, s, OH), 1.86-1.91 (4H, m,H-6b, H-18), 2.32 (2H, m, H-14), 2.39 (3H, s, 4-OAc), 2.40-2.59 (3H, m,H-6a, H-10, CH₂), 3.49 (1H, bs, OH), 3.82 (1H, d, J=7.0 Hz, H-3), 4.15(2H, d, J=8.5 Hz, H-20b), 4.29 (2H, H-2′, H-20a), 4.40 (1H, dd, J=6.0,10.5 Hz, H-7), 4.58 (1H, ddd, J=1.5, 9.0, 24.5 Hz, H-3′), 4.87 (1H, m,H-3′), 4.92 (1H, d, J=9.0 Hz, NH′-3′), 4.98 (1H, dd, J=1.5, 9.5 Hz,H-5), 5.62 (1H, d, J=7.5 Hz, H-2), 6.22 (1H, t, J=9.5 Hz, H-13), 6.31(1H, s, H-10), 7.45 (1H, t, J=8.0 Hz), 7.45 (1H, ddd, J=1.0, 2.0, 8.0Hz), 8.00 (1H, d, J=7.5 Hz), 8.12 (1H, s); ¹³C NMR (CDCl₃, 125 MHz) α8.9, 9.5, 14.9, 21.8, 22.2, 26.7, 27.5, 28.1, 35.5 (d, J=15.9 Hz), 43.2,45.7, 58.5, 72.2, 72.6, 73.1, 75.3, 75.5, 76.3, 79.2, 80.4, 81.0, 84.4,128.3, 130.1, 130.3, 130.9, 133.1, 133.7, 134.8, 142.1, 154.8, 165.7,170.2, 174.6, 203.6; ¹⁹F NMR (CDCl₃, 282 MHz) δ −84.14 (1F, dd, J=23.7,34.7 Hz), −86.13 (1F, d, J=36.7 Hz); HRMS (FAB⁺, 7 m/z): Calcd. forC₄₂H₅₂ClF₂NO₁₅.H⁺, 884.3066; Found 884.3057.

Example 193′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-chlorobenzoyl)-10-dimethylcarbamoyldocetaxel,SB-T-12854-4 (III-51n)

Yield 91%; white solid; mp ° C.; [α]_(D) ²⁰ −88.09 (c 2.1, CHCl₃); ¹HNMR (CDCl₃, 500 MHz): α 1.17 (3H, s, H-16), 1.27 (3H, m, H-17), 1.33(9H, s, Boc), 1.62 (1H, bs, OH), 1.69 (3H, s, H-19), 1.84 (1H, m, OH),1.90 (1H, ddd, J=2.5, 11.5, 17.5 Hz, H-6b), 1.93 (3H, s, H-18), 2.34(2H, m, H-14), 2.42 (3H, s, 4-OAc), 2.56 (1H, ddd, J=6.0, 9.0, 15.0 Hz,H-6a), 2.98 (3H, s, N-Me), 3.06 (3H, s, N-Me), 3.25 (1H, d, J=2.5 Hz,OH), 3.52 (1H, d, J=5.5 Hz, OH), 3.83 (1H, d, J=7.0 Hz, H-3), 4.18 (1H,d, J=8.5 Hz, H-20b), 4.29 (1H, s, H-2′), 4.32 (1H, d, J=8.5 Hz, H-20a),4.46 (1H, dd, J=6.5, 11.0 Hz, H-7), 4.58 (1H, ddd, J=1.5, 10.0, 24.5 Hz,H-3′vinyl), 4.93 (2H, m, H-3′, NH-3′), 5.01 (1H, d, J=10.0 Hz, H-5),5.63 (1H, d, J=7.5 Hz, H-2), 6.25 (1H, t, J=9.0 Hz, H-13), 6.27 (1H, s,H-10), 7.47 (2H, t, J=7.5 Hz), 7.49 (1H, dd, J=1.0, 9.5 Hz), 7.82 (1H,d, J=8.0 Hz), 8.15 (1H, s); ¹³C NMR (CDCl₃, 125 MHz) α 9.3, 14.9, 22.2,26.9, 28.1, 35.4 (d, J=6.0 Hz), 36.0, 36.6, 43.2, 45.5, 58.5, 72.4,72.6, 73.1, 75.6, 76.1, 76.3, 79.3, 80.4, 81.1, 84.6, 128.3, 130.1,130.4, 130.9, 133.3, 133.7, 134.8, 142.6, 154.8, 156.1, 165.7, 171.1,205.5; ¹⁹F NMR, (CDCl₃, 282 MHz) δ −84.16 (1F, dd, J=23.9, 34.9 Hz),−86.17 (1F, d, J=36.7 Hz); HRMS (FAB+, m/z): Calcd. forC₄₂H₅₃ClF₂N₂O₁₅.H⁺, 899.3175; Found 899.3151.

Example 203′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-chlorobenzoyl)-10-methoxycarbonyldocetaxel,SB-T-12855-4 (III-51o)

Yield 70%; white solid; [α]_(D) ²⁰ −72.09 (c 4.3, CHCl₃); ¹H NMR (CDCl₃,500 MHz): α 1.16 (3H, s, H-16), 1.26 (3H, m, H-17), 1.32 (9H, s, Boc),1.63 (1H, bs, OH), 1.71 (3H, s, H-19), 1.91 (1H, m, H-6b), 1.94 (3H, s,H-18), 2.33 (2H, d, J=9.0 Hz, H-14), 2.42 (3H, s, 4-OAc), 2.46 (1H, d,J=4.0 Hz, OH), 2.59 (1H, ddd, J=7.5, 10.0, 15.5 Hz, H-6a), 3.46 (1H,J=6.0 Hz, OH), 3.81 (1H, d, J=7.0 Hz, H-3), 3.87 (3H, s, H-10-MeO), 4.17(1H, d, J=8.5 Hz, H-20b), 4.29 (1H, d, J=5.5 Hz, H-2′), 4.32 (1H, d,J=8.5 Hz, H-20a), 4.39 (1H, m, H-7), 4.59 (1H, dd, J=8.0, 24.5 Hz, H-3′vinyl), 4.89 (2H, m, H-3′, NH-3′), 5.00 (1H, d, J=8.5 Hz, H-5), 5.64(1H, d, J=7.5 Hz, H-2), 6.13 (1H, s, H-10), 6.23 (2H, t, J=8.5 Hz,H-13), 7.49 (1H, t, J=8.0 Hz), 7.60 (1H, d, J=7.5 Hz,), 8.01 (1H, d,J=8.0 Hz), 8.14 (1H, s); ¹³C NMR (CDCl₃, 125 MHz) α 9.4, 14.9, 21.7,22.2, 26.6, 28.1, 35.3, 35.6, 43.1, 45.6, 55.6, 58.5, 72.1, 72.5, 73.2,75.4, 76.3, 78.2, 79.2, 80.5, 80.9, 84.4, 128.3, 130.1, 130.3, 130.9,132.6, 133.7, 134.9, 143.1, 154.9, 155.7, 165.7, 170.2, 203.8; ¹⁹F NMR(CDCl₃, 282 MHz) δ −84.16 (1F, dd, J=23.7, 34.7 Hz), −86.17 (1F, dd,J=34.9 Hz); HRMS (FAB⁺, m/z): Calcd. for C₄₁H₅₀ClF₂NO₁₆.H⁺, 886.2859;Found 886.2845.

Example 213′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-methoxybenzoyl)-10-acetyldocetaxel,SB-T-12851-1 (III-51p)

Yield 76%; white solid; [α]_(D) ²⁰ −74.42 (c 2.15, CHCl₃); ¹H NMR(CDCl₃, 400 MHz): α 1.15 (3H, s, C-16), 1.26 (3H, m, C-17), 1.30 (9H, s,Boc), 1.68 (3H, s, H-19), 1.76 (1H, s, OH), 1.88 (4H, m, H-6b, H-18),2.24 (3H, s, 10-OAc), 2.33 (2H, m, H-14), 2.38 (3H, s, 4-OAc), 2.49 (1H,d, J=3.5 Hz, OH), 2.56 (1H, ddd, J=6.5, 9.5, 15.0 Hz, H-6a), 3.47 (1H,J=4.5 Hz, OH), 3.81 (1H, d, J=7.5 Hz, H-3), 3.90 (3H, s, 2-m-MeO), 4.15(1H, d, J=8.0 Hz, H-20b), 4.27 (1H, s, H-2′), 4.36 (1H, d, J=8.0 Hz,H-20a), 4.41 (1H, dd, J=6.0, 10.5 Hz, H-7), 4.58 (1H, ddd, J=1.0, 9.5,24.5 Hz, H-3′vinyl), 4.87-4.93 (2H, m, H-3′, NH-3′), 4.97 (1H, dd,J=2.0, 9.0, H-5), 5.67 (1H, d, J=7.5 Hz, H-2), 6.24 (1H, t, J=8.5 Hz,H-13), 6.30 (1H, s, H-10), 7.15 (1H, dd, J=2.0, 8.0 Hz), 7.40 (1H, t,J=7.5 Hz), 7.45 (1H, s), 7.72 (1H, d, J=8.0 Hz); ¹³C NMR (CDCl₃, 100MHz) α 9.5, 14.8, 20.8, 21.8, 22.3, 26.7, 28.1, 35.5 (d, J=12.2 Hz),43.2, 45.6, 55.3, 58.5, 72.1, 72.7, 73.1, 75.1, 75.5, 76.4, 77.2, 79.0,80.5, 81.2, 84.4, 114.0, 120.7, 122.7, 129.7, 130.3, 133.1, 142.1,154.8, 159.7, 166.9, 170.2, 171.2, 203.5; ¹⁹F NMR (CDCl₃, 282 MHz) δ−84.55 (1F, dd, J=33.8, 36.4 Hz), −86.24 (1F, dd, J=36.4 Hz); HRMS(FAB⁺, m/z): Calcd. for C₄₂H₅₃F₂NO₁₆.H⁺, 866.3405; Found, 866.3439.

Example 223′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-methoxybenzoyl)-10-cyclopropanecarbonyldocetaxel,SB-T-12852-1 (III-51 q)

Yield 99%; white solid; [α]_(D) ²⁰ −77.03 (c 5.79, CHCl₃); ¹H NMR(CDCl₃, 500 MHz): α 0.99 (2H, m, CH₂-c-Pr), 1.10 (2H, m, CH₂-c-Pr), 1.15(3H, s, C-16), 1.25 (3H, m, C-17), 1.28 (9H, s, Boc), 1.66 (3H, s,H-19), 1.74-1.81 (2H, m, CH-c-Pr, OH), 1.83-1.89 (1H, m, H-6b), 1.87(3H, s, H-18), 2.31 (2H, m, H-14), 2.37 (3H, s, 4-OAc), 2.53 (1H, ddd,J=6.5, 9.5, 15.0 Hz, H-6a), 2.59 (1H, d, J=3.5 Hz, OH), 3.55 (1H, bs,OH), 3.79 (1H, d, J=7.5 Hz, H-3), 3.88 (3H, s, m-MeO-H-2), 4.16 (1H, d,J=8.5 Hz, H-20b), 4.26 (1H, d, J=2.5 Hz, H-2′), 4.34 (1H, d, J=8.5 Hz,H-20a), 4.40 (1H, m, H-7), 4.57 (1H, dd, J=10.0, 24.5 Hz, H-3′ vinyl),4.86 (1H, t, J=8.5 Hz, H-3′), 4.96 (2H, m, H-5, NH′), 5.65 (1H, d, J=7.0Hz, H-7), 6.23 (1H, t, J=9.0 Hz, H-13), 6.28 (1H, s, H-10), 7.13 (1H,ddd, J=2.0, 3.0, 8.0 Hz), 7.38 (2H, t, J=7.5 Hz), 7.63 (1H, s), 7.79(1H, d, J=7.5 Hz); ¹³C NMR (CDCl₃, 125 MHz) α 9.2, 9.4, 9.5, 13.0, 14.8,22.0, 22.3 (d, J=2.9 Hz), 26.7, 28.1, 35.5, (d, J=4.3 Hz), 43.2, 45.6,55.3, 58.5, 72.1, 72.6, 73.1, 75.1, 75.3, 76.4, 77.2, 79.0, 80.4, 81.0,84.4, 114.0, 120.6, 122.7, 129.7, 130.3, 133.2, 142.1, 154.8, 156.4,159.7, 166.9, 170.2, 172.4, 175.1, 203.8; ¹⁹F NMR (CDCl₃, 282 MHz) δ−84.62 (1F, dd, J=25.7, 36.7 Hz), −86.29 (1F, d, J=36.4 Hz); HRMS (FAB⁺,m/z): Calcd. for C₄₄H₅₅F₂NO₁₆.H⁺, 892.3562; Found, 892.3599.

Example 233′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-methoxybenzoyl)-10-propanoyldocetaxel.SB-T-12853-1 (III-51r):

Yield 58%; white solid; [α]_(D) ²⁰ −79.78 (c 3.66, CHCl₃); ¹H NMR(CDCl₃, 500 MHz): α 1.15 (3H, s, H-16), 1.22-1.25 (6H, m, H-17,H-10-CH₃), 1.30 (9H, s, Boc), 1.67 (3H, s, H-19), 1.71 (1H, s, OH), 1.79(1H, s, OH), 1.86-1.91 (4H, m, H-6b, H-18), 2.32 (2H, m, H-14), 2.38(3H, s, 4-OAc), 2.38-2.59 (3H, m, H-6a, H-10, CH₂), 3.52 (1H, bs, OH),3.82 (1H, d, J=7.0 Hz, H-3), 3.89 (H, m-MeO-H2), 4.18 (2H, d, J=8.5 Hz,H-20b), 4.27 (1H, H-2′), 4.35 (1H, d, J=8.5 Hz, H-20a), 4.40 (1H, dd,J=6.5, 11.0 Hz, H-7), 4.58 (1H, ddd, J=1.5, 10.0, 25.0 Hz, H-3′), 4.87(1H, t, J=9.0 Hz, H-3′), 4.96 (2H, m, NH′-3′, H-5), 5.66 (1H, d, J=6.5Hz, H-2), 6.24 (1H, t, J=9.0 Hz, H-13), 6.31 (1H, s, H-10), 7.15 (1H,ddd, J=1.0, 2.5, 8.5 Hz), 7.39 (1H, t, J=7.5 Hz), 7.65 (1H, s), 7.71(1H, d, J=8.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) α 9.0, 9.5, 14.8, 21.9,22.3, 26.7, 27.5, 28.1, 35.4 (d, J=15.9 Hz), 43.2, 45.6, 55.3, 58.3,72.1, 72.6, 73.1, 75.1, 75.3, 76.4, 77.2, 79.0, 81.1, 84.4, 114.0,122.7, 129.7, 130.3, 133.2, 141.9, 154.8, 159.7, 166.9, 170.2, 174.6,203.7; ¹⁹F NMR, (CDCl₃, 282 MHz) δ −84.58 (1F, dd, J=25.7, 36.7 Hz),−86.26 (1F, d, J=36.7 Hz); HRMS (FAB⁺, m/z): Calcd. for C₄₃H₅₅F₂NO₁₆.H⁺,880.3562; Found 880.3578.

Example 243′-dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-methoxybenzoyl)-10-dimethylcarbamate-docetaxel,ST-T-12854-1 (III-51s)

Yield 74%; white solid; ¹H NMR (CDCl₃, 500 MHz): α 1.15 (3H, s, H-16),1.25 (3H, s, H-17), 1.29 (9H, s, Boc), 1.67 (3H, s, H-19), 1.76 (1H, bs,OH), 1.88 (1H, m, H-6b), 1.89 (3H, s, H-18), 2.31 (2H, m, H-14), 2.38(3H, s, 4-OAc), 2.53 (1H, ddd, J=6.5, 10.0, 15.0 Hz, H-6a), 2.96 (3H, s,N-Me), 3.04 (3H, s, N-Me), 3.52 (1H, bs, OH), 3.81 (1H, d, J=7.0 Hz,H-3), 3.90 (3H, s, m-MeO-H2), 4.17 (1H, d, J=8.0 Hz, H-20b), 4.27 (1H,s, H-2′), 4.35 (1H, d, J=8.0 Hz, H-20a), 4.45 (1H, dd, J=6.0, 10.5 Hz,H-7), 4.58 (1H, ddd, J=1.5, 10.0, 25.0 Hz, H-3′vinyl), 4.87 (1H, t,J=8.5 Hz, H-3′), 4.97 (1H, m, H-5, NH-3′), 5.65 (1H, d, J=7.0 Hz, H-2),6.25 (2H, m, H-10, H-13), 7.14 (1H, dd, J=1.5, 7.5 Hz), 7.39 (2H, t,J=8.0 Hz), 7.65 (1H, s), 7.71 (1H, d, J=7.5 Hz); ¹³C NMR (CD+Cl₃, 125MHz) α 9.3, 14.9, 22.3, 26.9, 28.1, 35.4 (d, J=12.9 Hz), 36.0, 36.6,43.2, 45.5, 55.3, 58.5, 72.4, 72.7, 73.1, 75.2, 76.1, 76.4, 79.2, 80.4,81.2, 84.6, 114.0. 120.7, 122.7, 129.7, 130.3, 133.5, 133.7, 142.4,154.8, 156.1, 159.7, 166.9, 170.1, 205.6; ¹⁹F NMR (CDCl₃, 282 MHz) δ−84.60 (1F, dd, J=23.9, 34.9 Hz), −86.30 (1F, d, J=36.4 Hz); HRMS (FAB⁺,m/z): Calcd. For C₄₃H₅₆F₂N₂O₁₆.H⁺, 895.3671; Found 895.3676.

Example 253′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-methoxybenzoyl)-10-methoxycarbonyldocetaxel,SB-T-12855-1 (III-51t)

Yield 89%; white solid; [α]_(D) ²⁰ −68.98 (c 4.61, CHCl₃); ¹H NMR(CDCl₃, 500 MHz): α 1.15 (3H, s, H-16), 1.24 (3H, m, H-17), 1.29 (9H, s,Boc), 1.69 (3H, s, H-19), 1.78 (1H, bs, OH), 1.88 (1H, m, H-6b), 1.91(3H, s, H-18), 2.32 (2H, m, H-14), 2.38 (3H, s, 4-OAc), 2.49 (1H, d,J=4.5 Hz, OH), 2.56 (1H, ddd, J=7.0, 9.5, 15.0 Hz, H-6a), 3.53 (1H,J=5.5 Hz, OH), 3.78 (1H, d, J=6.5 Hz, H-3), 3.87 (3H, s, H-10-MeO), 3.89(3H, s, 7n-MeO-H2), 4.18 (1H, d, J=8.5 Hz, H-20b), 4.27 (1H, d, J=3.0Hz, H-2′), 4.36 (1H, d, J=8.5 Hz, H-20a), 4.41 (1H, m, H-7), 4.59 (1H,dd, J=9.5, 24.5 Hz, H-3′ vinyl), 4.86 (1H, t, J=9.0 Hz, H-3′), 4.95 (2H,m, H-5, NH-3′), 5.66 (1H, d, J=7.5 Hz, H-2), 6.12 (1H, s, H-10), 6.24(1H, t, J=8.5 Hz, H-13), 7.15 (1H, d, J=2.0, 7.5 Hz), 7.39 (1H, t, J=8.0Hz), 7.64 (1H, s), 7.71 (1H, d, J=7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) α9.5, 14.9, 21.8, 22.3, 26.6, 28.1, 35.3 (d, J=22.0 Hz), 43.1, 45.6,55.6, 55.6, 58.5, 72.0, 72.6, 73.1, 75.0, 77.2, 78.2, 79.0, 80.5, 81.1,84.4, 114.0, 120.7, 129.7, 130.3, 132.8, 142.9, 154.8, 155.7, 159.7,166.9, 170.3, 203.9; ¹⁹F NMR (CDCl₃, 282 MHz) δ −84.60 (1F, dd, J=25.7,36.7 Hz), −86.27 (1F, dd, J=36.7 Hz); HRMS (FAB⁺, m/z): Calcd. forC₄₂H₅₃F₂NO₁₇.H⁺, 882.3354; Found 882.3353.

Example 263′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-azidobenzoyl)-10-acetyldocetaxel,SB-T-12851-3 (III-51u)

Yield 49%; white solid; [α]_(D) ²⁰ −70.59 (c 3.23, CHCl₃); ¹H NMR(CDCl₃, 400 MHz): α 1.15 (3H, s, C-16), 1.26 (3H, s, C-17), 1.30 (9H, s,Boc), 1.67 (3H, s, H-19), 1.69 (1H, bs, OH), 1.88 (4H, m, H-6b, H-18),2.24 (3H, s, 10-OAc), 2.32 (2H, m, H-14), 2.39 (3H, s, 4-OAc), 2.49 (1H,bs, OH), 2.56 (1H, ddd, J=7.0, 9.5, 15.0 Hz, H-6a), 3.48 (1H, J=4.0 Hz,OH), 3.82 (1H, d, J=7.0 Hz, H-3), 4.16 (1H, d, J=8.5 Hz, H-20b), 4.26(1H, s, H-2′), 4.33 (1H, d, J=8.5 Hz, H-20a), 4.42 (1H, dd, J=6.5, 10.5Hz, H-7), 4.57 (1H, ddd, J=1.5, 9.5, 25.0 Hz, H-3′vinyl), 4.85 (1H, t,J=8.5 Hz, H-3′), 4.93 (1H, d, J=9.5 Hz, NH-3′), 4.98 (1H, d, J=7.5,H-5), 5.66 (1H, d, J=7.5 Hz, H-2), 6.22 (1H, t, J=9.0 Hz, H-13), 6.29(1H, s, H-10), 7.23 (1H, dd, J=1.5, 8.0 Hz), 7.48 (1H, t, J=8.0 Hz),7.81 (1H, s), 7.89 (1H, d, J=8.0 Hz); ¹³C NMR (CDCl₃, 100 MHz) α 9.5,14.9, 20.8, 21.9, 22.4, 26.7, 28.1, 35.5 (d, J=15.1 Hz), 43.2, 45.6,58.5, 72.1, 72.6, 73.1, 75.4, 75.5, 76.4, 79.1, 80.4, 81.0, 84.4, 120.1,124.4, 126.7, 130.2, 133.0, 140.9, 142.2, 154.8, 166.1, 170.3, 171.2,203.6; ¹⁹F NMR, (CDCl₃, 282 MHz) δ −83.99 (1F, dd, J=25.7, 36.7 Hz),−86.12 (1F, d, J=35.0 Hz); HRMS (FAB⁺, m/z): Calcd. forC₄₁H₅₀F₂N₄O₁₅.H⁺, 877.3314; Found, 877.3351.

Example 273′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-azidobenzoyl)-10-cyclopropanecarbonyldocetaxel,SB-T-12852-3 (III-51w)

Yield 78%; white solid; [α]_(D) ²⁰ −67.39 (c 5.09, CHCl₃); ¹H NMR(CDCl₃, 400 MHz): α 1.02 (2H, m, CH₂-c-Pr), 1.15 (2H, m, CH₂-c-Pr), 1.17(3H, s, C-16), 1.28 (3H, m, C-17), 1.32 (9H, s, Boc), 1.68 (3H, s,H-19), 1.76 (1H, bs, OH), 1.79 (1H, m, CH-c-Pr), 1.86-1.91 (1H, m,H-6b), 1.90 (3H, s, H-18), 2.34 (2H, m, H-14), 2.41 (3H, s, 4-OAc), 2.56(1H, ddd, J=6.5, 9.5, 15.0 Hz, H-6a), 2.62 (1H, bs, OH), 3.54 (1H, d,J=5.5 Hz, OH), 3.83 (1H, d, J=7.5 Hz, H-3), 4.18 (1H, d, J=8.5 Hz,H-20b), 4.28 (1H, d, J=3.0 Hz, H-2′), 4.35 (1H, d, J=8.5 Hz, H-20a),4.43 (1H, dd, J=6.5, 10.0 Hz, H-7), 4.58 (1H, ddd, J=1.5, 9.0, 24.5 Hz,H-3′ vinyl), 4.87 (1H, t, J=8.5 Hz, H-3′), 4.98 (2H, m, H-5, NH-3′),5.67 (1H, d, J=7.0 Hz, H-7), 6.24 (1H, t, J=8.0 Hz, H-13), 6.31 (1H, s,H-10), 7.25 (1H, dd, J=1.5, 8.0 Hz), 7.49 (2H, t, J=8.0 Hz), 7.82 (1H,s), 7.90 (1H, d, J=8.0 Hz); ¹³C NMR (CDCl₃, 100 MHz) α 9.2, 9.4, 9.5,13.0, 14.9, 22.0, 22.3, 26.7, 28.1, 35.5, (d, J=7.6 Hz), 43.2, 45.6,58.5, 72.1, 72.6, 73.1, 75.3, 75.5, 76.4, 79.1, 80.4, 81.0, 84.5, 120.1,124.4, 126.7, 130.2, 130.8, 133.1, 140.9, 142.3, 154.8, 166.1, 170.3,175.1, 203.7; ¹⁹F NMR (CDCl₃, 282 MHz) δ −84.02 (1F, dd, J=25.7, 34.9Hz), −86.14 (1F, d, J=34.9 Hz); HRMS (FAB⁺, m/z): Calcd. forC₄₃H₅₂F₂N₄O₁₅.H⁺, 903.3470; Found, 903.3469.

Example 283′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-azidobenzoyl)-10-propanoyldocetaxel,SB-T-12853-3 (III-51×)

Yield 93%; white solid; [α]_(D) ²⁰ −67.77 (c 3.32, CHCl₃); ¹H NMR(CDCl₃, 500 MHz): α 1.14 (3H, s, H-16), 1.22-1.25 (6H, m, H-17,H-10-CH₃), 1.30 (9H, s, Boc), 1.67 (3H, s, H-19), 1.71 (1H, s, OH), 1.69(1H, s, OH), 1.85-1.91 (4H, m, H-6b, H-18), 2.32 (2H, m, H-14), 2.39(3H, s, 4-OAc), 2.47-2.59 (3H, m, H-6a, H-10, CH₂), 3.48 (1H, d, J=4.5Hz, OH), 3.82 (1H, d, J=7.5 Hz, H-3), 4.16 (1H, d, J=8.5 Hz, H-20b),4.26 (1H, H-2′), 4.33 (1H, d, J=8.5 Hz, H-20a), 4.43 (1H, dd, J=7.0,11.0 Hz, H-7), 4.56 (1H, ddd, J=1.5, 9.0, 24.5 Hz, H-3′), 4.86 (1H, t,J=8.0 Hz, H-3′), 4.92 (1H, d, J=9.5 Hz, NH′-3′), 4.98 (1H, d, J=8.0 Hz,H-5), 5.66 (1H, d, J=7.5 Hz, H-2), 6.22 (1 H, t, J=8.0 Hz, H-13), 6.31(1H, s, H-10), 7.23 (1H, dd, J=1.5, 7.5 Hz), 7.48 (1H, t, J=7.5 Hz),7.81 (1H, s), 7.89 (1H, d, J=8.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) α 9.0,9.5, 14.9, 21.7, 22.4, 26.7, 27.5, 28.1, 35.5 (d, J=11.5 Hz), 43.2,45.6, 58.5, 72.1, 72.6, 73.1, 75.1, 75.3, 75.4, 76.4, 79.1, 81.0, 84.5,120.1, 124.4, 126.7, 130.2, 130.8, 133.2, 140.9, 154.8, 159.7, 166.1,170.3, 174.6, 203.7; ¹⁹F NMR (CDCl₃, 282 MHz) δ −83.99 (1F, dd, J=25.7,34.7 Hz), −86.12 (1F, d, J=36.7 Hz); HRMS (FAB⁺, m/z): Calcd. forC₄₂H₅₂F₂N₄O₁₅.H⁺, 891.3470; Found 891.3473.

Example 293′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-azidobenzoyl)-10-dimethylcarbamoyldocetaxel,SB-T-12854-3 (III-51y)

Yield 79%; white solid; [α]_(D) ²⁰ −75.39 (c 4.51, CHCl₃); ¹H NMR(CDCl₃, 500 MHz): α 1.15 (3H, s, H-16), 1.25 (3H, s, H-17), 1.30 (9H, s,Boc), 1.66 (3H, s, H-19), 1.75 (1H, bs, OH), 1.87 (1H, m, H-6b), 1.90(3H, s, H-18), 2.31 (2H, m, H-14), 2.39 (3H, s, 4-OAc), 2.54 (1H, ddd,J=7.0, 10.0, 15.5 Hz, H-6a), 2.96 (3H, s, N-Me), 3.04 (3H, s, N-Me),3.56 (1H, bs, OH), 3.81 (1H, d, J=7.0 Hz, H-3), 4.16 (1H, d, J=8.5 Hz,H-20b), 4.27 (1H, s, H-2′), 4.32 (1H, d, J=8.5 Hz, H-20a), 4.45 (1H, dd,J=6.5, 10.5 Hz, H-7), 4.57 (1H, ddd, J=1.0, 9.0, 24.0 Hz, H-3′vinyl),4.85 (1H, t, J=8.0 Hz, H-3′), 4.97 (2H, m, H-5, NH-3′), 5.65 (1H, d,J=7.0 Hz, H-2), 6.23 (1H, t, J=9.5 Hz, H-13), 6.25 (1H, s, H-10), 7.23(1H, dd, J=1.5, 8.5 Hz), 7.47 (1H, t, J=8.0 Hz), 7.80 (1H, s), 7.89 (1H,d, J=8.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) α 9.3, 14.9, 22.3, 26.9, 28.1,35.4 (d, J=6.6 Hz), 36.0, 36.6, 43.2, 58.5, 72.4, 72.6, 73.1, 75.6,76.1, 76.3, 79.2, 80.1, 84.7, 120.7, 120.2, 124.3, 126.7, 130.2, 130.9,133.4, 140.9, 142.6, 154.9, 156.1, 166.1, 170.3, 205.5; ¹⁹F NMR (CDCl₃,282 MHz) δ −84.06 (1F, dd, J=25.7, 34.7 Hz), −86.17 (1F, d, J=36.7 Hz);HRMS (FAB⁺, m/z): Calcd. for C₄₂H₅₃F₂N₅O₁₅.H⁺, 906.3579; Found 906.3588.

Example 303′-Dephenyl-3′-(2,2-difluorovinyl)-2-debenzoyl-2-(3-azidobenzoyl)-10-methoxycarbonyldocetaxel,SB-T-12855-3 (III-51z)

Yield 77%; white solid; [α]D²⁰ −66.67 (c 3.9, CHCl₃); ¹H NMR (CDCl₃, 400MHz): α 1.15 (3H, s, H-16), 1.24 (3H, s, H-17), 1.29 (9H, s, Boc), 1.69(3H, s, H-19), 1.71 (1H, bs, OH), 1.89 (1H, m, H-6b), 1.92 (3H, s,H-18), 2.32 (2H, m, H-14), 2.39 (3H, s, 4-OAc), 2.49 (1H, bs, OH), 2.56(1H, ddd, J=6.5, 9.5, 14.5 Hz, H-6a), 3.51 (1H, bs, OH), 3.79 (1H, d,J=7.0 Hz, H-3), 3.87 (3H, s, H-10-MeO), 4.17 (1H, d, J=8.5 Hz, H-20b),4.26 (1H, s, H-2′), 4.33 (1H, d, J=8.5 Hz, H-20a), 4.40 (1H, dd, J=7.0,11.0 Hz, H-7), 4.57 (1H, ddd, J=1.0, 9.0, 24.5 Hz, H-3′ vinyl), 4.85(1H, t, J=8.5 Hz, H-3′), 4.96 (2H, m, H-5, NH-3′), 5.66 (1H, d, J=7.5Hz, H-2), 6.12 (1H, s, H-10), 6.22 (1H, t, J=9.0 Hz, H-13), 7.23 (1H,dd, J=1.5, 6.5 Hz), 7.48 (1H, t, J=7.5 Hz), 7.81 (1H, s), 7.89 (1H, d,J=8.0 Hz); ¹³C NMR (CDCl₃, 100 MHz) α 9.5, 14.9, 21.8, 22.4, 26.6, 28.1,35.4 (d, J=18.6 Hz), 43.1, 45.6, 55.6, 55.6, 58.5, 72.0, 72.5, 73.1,75.4, 76.3, 78.2, 79.1, 80.4, 81.0, 84.3, 120.1, 124.4, 126.7, 130.2,130.8, 132.7, 140.9, 143.0, 154.7, 155.7, 166.1, 170.4, 203.8; ¹⁹F NMR(CDCl₃, 282 MHz) δ −84.01 (1F, dd, J=25.7, 36.7 Hz), −86.13 (1F, d,J=36.7 Hz); HRMS (FAB⁺, m/z): Calcd. for C₄₁H₅₀F₂N₄O₁₆.H⁺, 893.3263;Found 893.3269.

Example 31 Tumor Growth Inhibitory Activity of Fluorotaxoids

Fluorotaxoids were evaluated in their tumor growth inhibitory activitiesagainst human tumor cell lines, MCF7 (mammary carcinoma) or MCF7-R(mammary carcinoma cells 250-fold resistant to paclitaxel), after 72 hdrug exposure according to literature methods. Results are shown forsome selected compounds in the tables below.

In the tables, lower numbers indicate higher potency (or greateractivity). Paclitaxel was used as the standard for comparison. The datarepresent the mean values of at least three separate experiments.

Example 31a

Cytotoxicity (IC₅₀ nM) of CF₂═CH-Taxoids (1)

MCF7 MCF7-R CF₂═CH-Taxoid R X (breast) (breast) R/S Paclitaxel Me H 1.2300 250 SB-T-12851 Me H 0.099 0.95 9.6 SB-T-12852 cyclo-Pr H 0.12 6.0353 SB-T-12853 Et H 0.12 1.2 10 SB-T-12854 Me₂N H 0.13 4.27 33 SB-T-12855MeO H 0.14 1.29 9.2

Example 31b

Cytotoxicity (IC₅₀ nM) of CF₂═CH-Taxoids (2)

MCF7 MCF7-R CF₂═CH-Taxoid R X (breast) (breast) R/S Paclitaxel Me H 1.2300 250 SB-T-12851-1 Me MeO 0.25 1.5 6.0 SB-T-12852-1 cyclo-Pr MeO 0.0920.48 5.2 SB-T-12853-1 Et MeO 0.34 0.57 1.7 SB-T-12854-1 Me₂N MeO 0.110.96 8.7 SB-T-12855-1 MeO MeO 0.078 0.50 6.4

Example 31c

Cytotoxicity (IC₅₀ nM) of CF₂═CH-Taxoids (3)

MCF7 MCF7-R CF₂═CH-Taxoid R X (breast) (breast) R/S Paclitaxel Me H 1.2300 250 SB-T-12851-2 Me F 0.13 1.53 12 SB-T-12852-2 cyclo-Pr F 0.0761.72 23 SB-T-12853-2 Et F 0.23 2.54 11 SB-T-12854-2 Me₂N F 0.17 2.25 9.4SB-T-12855-2 MeO F 0.12 1.85 11

Example 31d

Cytotoxicity (IC₅₀ nM) of CF₂═CH-Taxoids (4)

MCF7 MCF7-R CF₂═CH-Taxoid R X (breast) (breast) R/S Paclitaxel Me H 1.2300 250 SB-T-12851-3 Me N₃ 0.092 0.34 3.7 SB-T-12852-3 cyclo-Pr N₃ 0.0920.45 4.9 SB-T-12853-3 Et N₃ 0.13 0.38 2.9 SB-T-12854-3 Me₂N N₃ 0.13 0.453.7 SB-T-12855-3 MeO N₃ 0.076 0.40 5.3

Example 31e

Cytotoxicity (IC₅₀ nM) of CF₂═CH-Taxoids (5)

MCF7 MCF7-R CF₂═CH-Taxoid R X (breast) (breast) R/S Paclitaxel Me H 1.2300 250 SB-T-12851-4 Me Cl 0.13 0.70 5.4 SB-T-12852-4 cyclo-Pr Cl 0.120.50 4.2 SB-T-12853-4 Et Cl 0.13 0.45 3.5 SB-T-12854-4 Me₂N Cl 0.93 2.62.8 SB-T-12855-4 MeO Cl 0.099 1.15 12

Assessment of cell growth inhibition was determined according to themethods of Skehan et al (See Skehan et al., J. Nat. Cancer Inst., 82,1107 (1990)). Briefly, cells were plated between 400 and 1200 cells/wellin 96 well plates and incubated at 37° C. for 15-18 h prior to drugaddition to allow attachment of cells. Compounds tested were solubilizedin 100% DMSO and further diluted in RPMI-1640 containing mM HEPES. Eachcell line was treated with 10 concentrations of compounds (5 log range).After a 72 h incubation, 100 μL of ice-cold 50% TCA was added to eachwell and incubated for 1 h at 4° C. Plates were then washed 5 times withtap water to remove TCA, low-molecular-weight metabolites and serumproteins. Sulforhodamine B (SRB) (0.4%, 50 μL) was added to each well.Following a 5 minute incubation at room temperature, plates were rinsed5 times with 0.1% acetic acid and air dried. Bound dye was solubilizedwith 10 mM Tris Base (pH 10.5) for 5 min on a gyratory shaker. Opticaldensity was measured at 570 nm.

Data were fit with the Sigmoid-Emax concentration-effect model withnon-linear regression, weighted by the reciprocal of the square of thepredicted response (see Holford, N. H. G.; Scheiner, L. B.,“Understanding the dose-effect relationship: Clinical applications ofpharmaco-kinetic-pharmacodynamic models,” Clin. Pharmacokin., 6, 429-453(1981)). The fitting software was developed by the Roswell Park CancerInstitute with Microsoft FORTRAN, and uses the Marquardt algorithm (seeMarquardt, D. W., “An algorithm for least squares estimation ofnonlinear parameters,” J. Soc. Ind. Appl. Math., 11, 431-441 (1963)) asadopted by Nash for the non-linear regression (see Nash, J. C., “Compactnumerical method for computers: Linear algebra and functionminimization,” John Wiley & Sons, New York, 1979). The concentration ofdrug which resulted in 50% growth inhibition (IC₅₀) was calculated.

Thus, while there have been described what are presently believed to bethe preferred embodiments of the present invention, those skilled in theart will realize that other and further embodiments can be made withoutdeparting from the spirit of the invention, and it is intended toinclude all such further modifications and changes as come within thetrue scope of the claims set forth herein.

1. A taxoid compound represented by the formula:

wherein: R¹ represents an alkyl, alkenyl, alkylamino, dialkylamino, or alkoxy group having one to six carbon atoms; a non-aromatic carbocyclic alkyl or alkenyl group having three to seventeen ring carbon atoms; a carbocyclic aryl group having six to eighteen ring carbon atoms; a non-aromatic heterocyclic group having three to seventeen ring carbon atoms or a heterocyclic aryl group having five to seventeen ring carbon atoms, wherein said cyclic groups can be unfused or fused, and unsubstituted or substituted; R² represents a hydrogen; alkyl, alkenyl, alkoxy, alkenyloxy, acyloxy, alkylthio, alkenylthio, alkylamino or dialkylamino having one to six carbon atoms; halogen; fluoroalkyl group having one to three fluorine atoms and one to three carbon atoms; hydroxyl; carboxyl; amino or azido; R³ and R⁵ both represent hydrogen, or R³ and R⁵ are linked as a cyclic carbonate; R⁴ represents an alkyl or alkenyl group having one to six carbon atoms; or a cycloalkyl or cycloalkenyl group having three to seven ring carbon atoms; and R⁶ represents a fluorovinyl, difluorovinyl, or trifluorovinyl group having the formula

wherein R⁷, R⁸, and R⁹ each independently represent a hydrogen or fluoro group, provided that at least one of R⁷, R⁸, and R⁹ represents a fluoro group.
 2. The taxoid compound according to claim 1, wherein R⁷ represents hydrogen and each of R⁸ and R⁹ represents a fluoro group.
 3. The taxoid compound according to claim 1, wherein R⁴ represents tert-butyl.
 4. The taxoid compound according to claim 3, represented by the formula:

wherein R¹ represents an alkyl, alkenyl, alkylamino, dialkylamino, or alkoxy group having one to six carbon atoms; a non-aromatic carbocyclic allyl or alkenyl group having three to seventeen ring carbon atoms; a carbocyclic aryl group having six to eighteen ring carbon atoms; a non-aromatic heterocyclic group having three to seventeen ring carbon atoms or a heterocyclic aryl group having five to seventeen ring carbon atoms, wherein said cyclic groups can be unfused or fused, and unsubstituted or substituted; and wherein R² represents a hydrogen; alkyl, alkenyl, alkoxy, alkenyloxy, acyloxy, alkylthio, alkenylthio, allylamino or dialkylamino having one to six carbon atoms; halogen; fluoroalkyl group having one to three fluorine atoms and one to three carbon atoms; hydroxyl; carboxyl; amino or azido.
 5. The taxoid compound according to claim 4, wherein R¹ represents methyl, ethyl, methoxy, dimethylamino or cyclopropyl and R² represents hydrogen, methyl, methoxy, chloro, fluoro or azido.
 6. The taxoid compound according to claim 4, wherein R¹ represents methyl, ethyl, methoxy, dimethylamino or cyclopropyl and R² represents methoxy.
 7. The taxoid compound according to claim 4, wherein R¹ represents methyl, ethyl, methoxy, dimethylamino or cyclopropyl and R² represents azido.
 8. The taxoid compound according to claim 4, wherein R¹ represents methyl, ethyl, methoxy, dimethylamino or cyclopropyl and R² represents chloro.
 9. The taxoid compound according to claim 4, wherein R¹ represents methyl, ethyl, methoxy, dimethylamino or cyclopropyl and R² represents fluoro.
 10. A pharmaceutical composition comprising a taxoid compound according to claim 1 and a pharmaceutically acceptable carrier.
 11. A method for inhibiting the growth of cancer cells in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a taxoid compound according to claim
 1. 